Compositions and Methods for Treating Atopic Dermatitis

ABSTRACT

A method of treating atopic dermatitis and/or psoriasis comprising the application of select dilinoleate isohexides to the skin.

RELATED APPLICATION

The present application is a continuation of pending U.S. patentapplication Ser. No. 17/728,876, filed 25 Apr. 2022, which is adivisional application of U.S. patent application Ser. No. 16/791,732,filed 14 Feb. 2020, now U.S. Pat. No. 11,312,725, which is acontinuation of U.S. patent application Ser. No. 15/277,990, filed 22Sep. 2016, now U.S. Pat. No. 10,597,402, which a) claims the benefit ofU.S. Provisional Application Ser. No. 62/378,217 filed 23 Aug. 2016 andb) is a continuation-in-part of U.S. patent application Ser. No.15/081,898 filed 27 Mar. 2016, now U.S. Pat. No. 9,636,321, which claimsthe benefit of U.S. Provisional Application Ser. No. 62/139,619 filed 27Mar. 2015, the contents of all of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods with which toimprove skin barrier building and function, to repair epidermal injuryand rebuild the stratum corneum and skin barrier, and to defend andprotect skin function and integrity. Specifically, the application ofC₁₆ to C₂₀ mono- and/or di-esters of isosorbide to mammalian skin isfound to alter the expression of genes and modify and recalibrategenetic networks and cellular pathways in ways that promote and restoreskin health and mitigate skin damage. The present invention also relatesto the treatment of various skin diseases and conditions including,among others, those associated with reduced filaggrin production in skinsuch as ichthyosis vulgaris and/or susceptibility to other diseasesincluding atopic dermatitis (eczema), asthma, and allergies (includingfood allergy).

BACKGROUND OF THE INVENTION

The epidermis or outer layer of the skin is conventionally divided intofour distinct layers, each of which plays an important and key role inthe overall function and performance of the skin. Though characterizedas having distinct layers, the reality is that the keratinocytes andtheir associated structures, elements and the like, that make up eachlayer actually represent the successive generations of differentiatingkeratinocytes that have moved up from the bottom most layer to the skinsurface. The bottom layer is the basal layer of keratinocytes or basalcells which constitutes the germinal layer of the epidermis. Thekeratinocytes of the basal layer are of two types or function, one isthe terminally differentiating cells and the other the dividing cellswhich replicate themselves to form additional dividing cells and theterminally differentiating cells. The next layer is the spinous layer orstratum spinosum composed of several layers of polyhedral keratinocytes.It is in this layer that keratinization begins whereby thedifferentiating keratinocytes are actively engaged in synthesizingfibrilar proteins which eventually form the desmosomes which form strongconnections between adjacent keratinocytes: thus beginning the formationof the skin barrier. The next layer is the granular layer or stratumgranulosum which is composed of one to five layers of flattenedkeratinocytes whose nuclei are in the process of degenerating. At thispoint in their differentiation process, the keratinocytes containdistinct cytoplasmic inclusions, keratohyalin granules, andkeratinosomes, the latter of which help form the body's “intercellularcement” by spreading their lamellae into the spaces between cells.Keratohyalin helps make keratin more resistant and decomposes into amixture of amino acids that create the natural moisturizing factor(NMF). The final layer of the epidermis is the cornified layer orstratum corneum consisting of many, typically 15-20, layers of deadkeratinocytes, also known as corneocytes, at the terminal stage of theirdifferentiation. The corneocytes are flattened, cornified, non-nucleatedcells mainly consisting of a fibrous material containing cytokeratinsand surrounded by a cornified envelope. The corneocytes continuallyslough off or are worn off in a process typically referred todesquamation. Despite the continual loss of corneocytes, newkeratinocytes are continually being produced in the basal layer tocompensate for the continual loss of the corneocytes from the cornifiedlayer (J Clinical Investigation, 116(5):1150-1158, 2006).

As noted above, during the differentiation process the mitoticallyactive epidermal cells known as the terminally differentiating cellsmove from the basal layer through the spinous layer and the granularlayer towards the stratum corneum where they arrive as dead, flattenedsquames and are subsequently eliminated through desquamation. The wholeof this process is the subject of fine regulation under the control ofmultiple hormonal or cellular factors. In addition to celldifferentiation, a number of concurrent processes are running as wellduring which various proteins are expressed leading to additionalstructural and architectural elements key to the operation and functionof the epidermis. For example, crosslinking of various epidermalproteins eventually leads to the establishment of the cornifiedenvelope, a thick peripheral protein envelope that stabilizes eachcorneocyte. Structural proteins of the cornified envelope (CE) includeInvolucrin, Loricrin, Trichohyalin and the class of Small Proline-richProteins (SPPRs) constitute about 7-10% of the mass of the epidermis.Additionally, lipids are synthesized in lamellar granules which aresubsequently extruded into the extracellular space where they surroundthe corneocytes and build the lipid envelope. These structural proteinstogether with lipids (ceramides) form the complete barrier. Theseadditional elements move with the keratinocytes as well and form thestratum corneum which serves as an impermeable, insoluble, and highlyprotective fortress, preventing ingress of adverse environmental andother factors or elements and microorganisms and preventing the egressof essential body fluids, especially water, and solutes (J ClinicalInvestigation, 116(5):1150-1158, 2006).

The epidermal differentiation complex comprises approximately 60 geneslocated on chromosome 1q21 involved in epithelial differentiation whichplays key roles in keratinocyte differentiation and stratum corneumproperties (Front Biosci (Landmark Ed), 17:1517-1532, 2012; ExperimentalDermatology, 21:643-649, 2012). Apart from Involucrin and Loricrin, EDCalso contains “clusters” of related genes (J Invest Dermatol,124:1062-1070, 2005), such as S100 genes, Small proline rich protein(SPRPs) genes and Late Cornified Envelope (LCE) genes. Given thecomplexity of the epidermal differentiation process, it is no wonderthat many defects or disorders of the skin can be linked to disruptions,defects in, and modifications of these processes as well as variousimbalances in the hormonal, cellular or molecular mechanisms underlyingthe formation of the stratum corneum. For example, when theproliferation and/or differentiation of the cells of the basal layer ofthe epidermis is accelerated relative to desquamation, then the stratumcorneum tends to thicken. This dysfunction can, depending on its degreeof manifestation, be associated with various esthetic defects, such assigns of skin aging, an epidermal barrier function disorder, or signs ofdryness of the skin, or, where appropriate, with various pathologicaldisorders, for instance hyperkeratosis, xerosis, ichthyosis, psoriasisor reactive hyperkeratosis. Conversely, a slowing of the proliferationand/or differentiation of the cells of the basal layer relative todesquamation can manifest itself through thinning of the epidermis, andmore particularly of the cornified layer. This dysfunction can,depending on its degree of manifestation, be associated with variousesthetic defects, such as a healing defect, or a re-epithelializationdefect, in particular after a skin scrubbing or exfoliant treatment, or,where appropriate, with various pathological disorders, for instancereactions of immune origin, generally induced by contact of the skinwith one or more exogenous agents.

Again, as noted, the skin provides an effective barrier between theorganism, the human body, and the environment, preventing the invasionof pathogens and fending off chemical and physical assaults, as well asthe unregulated loss of water and solutes (Exp Dermatol, 17(12):10643-1072, 2008). The physical barrier is localized primarily in thestratum corneum and consists of protein-enriched cells (corneocytes withcornified envelope and cytoskeletal elements, as well ascorneodesmosomes) and lipid-enriched intercellular domains. Thenucleated epidermis, with its tight, gap and adherens junctions,additional desmosomes and cytoskeletal elements, also contributes to thebarrier. Lipids are synthesized in the keratinocytes during epidermaldifferentiation and are then extruded into the extracellular domains,where they form lipid-enriched extracellular layers. The cornified cellenvelope, a robust protein/lipid polymer structure, is located below thecytoplasmic membrane on the exterior of the corneocytes. Ceramidesforming the backbone for the subsequent addition of free ceramides, freefatty acids and cholesterol in the stratum corneum, are covalently boundto cornified envelope proteins. Filaggrin is cross-linked to thecornified envelope and aggregates keratin filaments into macrofibrils.Calcium ion also influences the formation and maintenance of barrierfunction. Adverse changes in lipid composition and epidermaldifferentiation lead to a disturbed skin barrier, which allows the entryof environmental allergens, immunological reaction and inflammation inatopic dermatitis. A disturbed skin barrier is a key indicator for andattribute of the pathogenesis of contact dermatitis, ichthyosis,psoriasis, and atopic dermatitis.

One of the key elements or structures of the epidermis responsible forits barrier function is the tight junctions (TJs). TJs are very complexstructures that are formed by transmembrane, plaque and scaffoldingproteins and have a plurality of distinct, yet somewhat interrelated,functions including permeability (barrier function), polarity (fencefunction), signaling (cell growth & differentiation), regulation (geneexpression & cell proliferation), and tumor suppression. Transmembraneproteins, that is, the family of claudins, occludins and the family ofjunctional adhesion molecules (JAMs), and scaffolding proteins, such asthe zonula occludins (ZO), are important for the formation andregulation of the permeability barrier and for the formation of amolecular fence that separates lipids from apical and basolateral partsof the cell; are contact sites for cell surface receptors, for example,TGF-β-receptor, and molecules of signal transduction pathways; and areinvolved in the interaction with cells of the immune system, forexample, neutrophils. They are often targets for pathogens and theirtoxins as well as allergens

Another key element or structure associated with barrier function andskin integrity is the desmosomes. Desmosomes are adhesive intercellularjunctions that attach cell surface adhesion proteins to intracellularkeratin filaments (E Delva et al, The Desmosomes, Cold Spring HarborPerspective in Biology, 2009, 1:a002543). Abnormality in thedesmosome-keratin filament complex leads to a breakdown in cell adhesion(fragility) and increase in Trans Epidermal Water Loss (TEWL). Keygenes/proteins involved in maintaining desmosome functions include:

-   -   Desmogleins & Desmocollins (members of the Cadherin super        family) which mediate adhesion at desmosomes; provide structural        integrity of the epidermis; and modulate keratinocyte        proliferation and differentiation;    -   Plakoglobin & Plakophillins which recruit intermediate filaments        to sites of desmosome assembly and maintain desmosomal integrity    -   Desmoplakin which mediate linkage to the cytoskeleton-pivotal in        the development of epidermis; and    -   Cadherin which mediates Ca²⁺-dependent contact between adjacent        cells and whose lack of expression causes separation of        keratinocytes & weakened desmosomal adhesion.

In light of the foregoing, it is clear that the “granular layerexpressing genes” have important roles in the final stage of epidermaldifferentiation, cornification and barrier function. Perhaps some of themore important granular layer expressing genes are those responsible forthe formation of filaggrin (filament-aggregating protein) which plays acrucial role in the formation of the corneocyte as well as thegeneration of its intracellular metabolites, which contribute to stratumcorneum hydration and pH (J Invest Dermatol, 132(3 Pt 2):751-762, 2012).The levels of filaggrin and its degradation products are influenced notonly by the filaggrin genotype but also by inflammation and exogenousstressors. Filaggrin deficiency is observed in patients with atopicdermatitis regardless of filaggrin mutation status, suggesting that theabsence of filaggrin is a key factor in the pathogenesis of this skincondition (J Allergy Clin Immunol, 134(4):792-799, 2014). Filaggrinbreakdown products form natural moisturizing factor, which plays acentral role in the hydration of the stratum corneum. Sequence analysisand epidemiological studies indicate that loss-of-function mutations inthe filaggrin gene, which is known to cause the autosomal dominant scalyskin disorder ichthyosis vulgaris, are major genetic predisposingfactors of atopic dermatitis. These findings established the ‘filaggrinhypothesis,’ which states that atopic dermatitis can be triggered by thechronic exposure of barrier-disrupted skin to percutaneous antigens dueto abnormalities in filaggrin (J Investigative Dermatology,126:1200-1202, 2006; Curr Probl Dermatol, 41:35-46, 20111). Filaggrinwas named by the late Peter Steinert, and its gene, FLG, is located withmany others involved in terminal differentiation, in the epidermaldifferentiation complex on chromosome 1q21 (J Invest Dermatol,126:1200-1202, 2006).

Maladies attributable to filaggrin imbalance are well known. Forinstance, filaggrin deficiency is found in one in ten Europeans and acomplete absence of filaggrin in one in 400 Europeans: both of whichaffect keratinocyte differentiation as well as compromise barrierformation and lead to mild or severe ichthyosis vulgaris. The varyingdegrees of impaired keratinocyte differentiation and barrier formationallow increased trans-epidermal water loss and, perhaps moreimportantly, increased entry of allergens, antigens, and chemicals fromthe environment. Thus, filaggrin-deficient individuals are chronicallyexposed to insult through the epidermis, which in many cases leads toinflammation of the skin—this is atopic dermatitis. Irvine and McLeanhypothesized that a percentage of these individuals go on to developasthma when allergens, to which their immune system has already beenprimed via cutaneous exposure, later enter the lungs; this is onepossible mechanism of atopic dermatitis-associated asthma (J InvestDermatol, 126:1200-1202, 2006). While some of this may be attributed togenetic mutations, genetic mutations are ancient and clearly cannotexplain the observed increase in atopic dermatitis and atopic disease inthe past two decades. These recent increases in the prevalence of atopicdermatitis must be caused, at least in part, through environmentalinfluences on the epithelial barrier. For example, different types ofheating systems (Environ Res, 81:151-158, 1999) and low-humidityenvironments are likely to exacerbate the effects of filaggrindeficiency and increase susceptibility to develop atopic dermatitis (orlower the threshold for developing it). Similar arguments may beadvanced regarding hard-water areas, increased use of detergents,environmental pollutants, increased washing, and many other influences.A corollary is that current efforts to intervene early and topotentially prevent the “atopic march” (Immunol Allergy Clin North Am,25:231-246, 2005) are now supported by additional evidence that warrantsa focused effort on improving barrier dysfunction (Acta DermatovenerolCroat, 22(4):313-315, 2014).

Another key protein of keratinocyte differentiation and barrier buildingand which affects and/or is involved in filaggrin development isskin-specific retroviral-like aspartic protease (SASPase). Matsui et.al. (EMBO Mol Med, 3(6):320-33, 2011) reported that SASPase deficiencyin hairless mice resulted in dry skin and a thicker and less hydratedstratum corneum with an accumulation of aberrantly processedprofilaggrin, a marked decrease of filaggrin, but no alteration in freeamino acid composition, compared with control hairless mice. Matsui etal further demonstrated that recombinant SASPase directly cleaved alinker peptide of recombinant profilaggrin. Furthermore, missensemutations were detected in 5 of 196 atopic dermatitis patients and 2 of28 normal individuals. Among these, the V243A mutation induced completeabsence of protease activity in vitro, while the V1871 mutation induceda marked decrease in its activity. These findings demonstrate thatSASPase activity is indispensable for processing profilaggrin andmaintaining the texture and hydration of the stratum corneum. Recently,Bernard et. al. have identified SASPase in the granular layer of humanepidermis (J Invest Dermatol, 125:156-159m 2005). A number of serine,cysteine, and aspartic proteases have been reported to be localized inthe stratum corneum and suggested to play a role in desquamation by thedegradation of cornedesmosomal proteins such as desmoglein 1,desmocollin 1, plakoglobin and corneodesmosin. It is possible thatSASPase partially degrades these proteins and regulates stratum corneumfunction (J Biol Chem, 281:27512-27525, 2006).

Following on the foregoing, it is to be remembered that in normalepidermis non-phosphorylated profilaggrin is orderly processed intofilaggrin and bundle keratin filaments at the lower stratum corneum,then degraded into free amino acids which constitute most of the naturalmoisturizing factors (NMFs) in the upper stratum corneum. SASPasedeficiency causes incomplete linker cleavage of profilaggrin resultingin an accumulation of trimeric and dimeric profilaggrins slightlydegraded from either N- or C-terminal ends in the lower stratum corneum.Such aberrant profilaggrin may bind to keratin filaments, finallydegrade, and produce a normal composition of free amino acids in theupper stratum corneum. Finally, the stratum corneum of SASPase deficientepidermis has an increased number of layers and produces a wrinkled,dry, rough skin (EMBO Mol Med, 3(6):320-33, 2011). These resultsindicate that activity of SASPase plays a key role in determining thetexture of the stratum corneum by modulating stratum corneum hydrationas well as profilaggrin to filaggrin processing.

The identification of reduced FLG expression in a range of dry, scalyskin disorders and the role SASPase plays therein as well indicates thatrestoring FLG expression to improve skin barrier function could be auseful therapeutic endeavor (Cutis, 84:2-15, 2009). For example, oneapproach would be to upregulate expression of the FLG gene. Thus,screening small molecules to identify compounds capable of increasingFLG expression might generate new products suitable for use in thetopical treatment of ichthyosis vulgaris as well as in the treatment ofa subset of individuals with atopic dermatitis. The unifying goal is todevelop topically applied FLG- and SASPase-promoting compounds, not justup-regulating either FLG or SASPase, that could surpass currenttherapies based on moisturizers, corticosteroids and otheranti-inflammatory compounds. These latter therapies, including potentcorticosteroids, influence the manifestation of the disease orinflammatory condition but fail to address the underlying problem and/orrepair of the barrier.

Clearly, barrier function, architecture and integrity are critical toproper skin function and condition. While a key role of the barrier isjust that, as a barrier, it also serves as a transport medium allowingfor transport of substances across the Stratum Corneum. The vastmajority of the very limited transport of substances across the StratumCorneum takes place through the lipid bilayer (Contact Dermatitis,58(5):255-62, 2008). The three major classes of stratum corneum (SC)lipids are the ceramides, free fatty acids and cholesterol, all of whichseem to have influence on (and are influenced by) the integrity of thestratum corneum, especially the ceramides and cholesterol. Meanwhile,the free fatty acids are believed to play a major role in the bilayerformation and pH. A number of external factors such as changes in airhumidity, sun exposure, detergents, moisturizers, etc. impact andinfluence the SC lipids. A recent paper has indicated that an increasein pH, especially in aged skin, of the stratum corneum leads to animpairment of the lipid processing (J Invest Dermatol, 127:2847-2856,2007). Concurrence is found in four additional papers that founddecreased levels of major lipids, in particular ceramides, in aged humanskin (J Invest Dermatol, 96:523-526, 1991; Arch Dermatol, 288:765-770,1996; Arch Dermatol Res, 288(12):765-770, 1996; Exp Dermatol,14(8):609-618, 2005). Seasonal changes are also found to affect thepresence and amount of various lipids (Arch Dermatol, 288:765-770, 1996;Dermatology, 188:207-214, 1994). Additionally, it has been shown that indiseases related to an impaired skin barrier such as atopic dermatitis,the level of some or all ceramides are decreased, while the level ofcholesterol is increased (Acta Derm Venereol, 78:27-30, 1998; J InvestDermatol, 96:523-526, 1991; Arch Dermatol Res, 28:219-223, 1991). Theexact consequence of this is not known, and more research is needed.

Though traditional therapies such as moisturizers, cortisone treatmentsand the like have long been employed in addressing various skinconditions, especially dryness, more recent efforts to address skinconditions are focused on therapies based on calcineurin inhibitors andlipid-containing emulsions which are found to support repair of variouselements and/or functions of the barrier. Bernard et. al. (U.S. Pat.Nos. 7,521,422; 7,888,315 and 9,290,553) teach the use of isolatedpeptides from skin aspartic proteases in cosmetics and therapeutics forimproving skin homeostasis and addressing esthetic defects orpathological disorders of the skin. Continuing on with their efforts,Bernard et. al. (US 2014/0005207) have also discovered that certaincomplex polyheterocyclic organic compounds suitable for modulating theinteraction between SASPase and filaggrin-2, or FLG2 or betweenhomologues, mutants, or fragments of said proteins, are also capable inaddressing esthetic defects or pathological disorders of the skin.Finally, Chaudhuri (U.S. Pat. No. 8,496,917) teaches that theapplication of certain esters and ethers of isohexide, particularly thecaprylic esters, to the skin improves skin hydration and barrierhomeostasis.

While progress is being made, there is still an urgent and growing needto identify therapeutic agents and actives that will combat themanifestation of various skin diseases and maladies.

Similarly, there is a continuing need to identify therapeutic agents andactives that will address the cause or underlying factors that lead tothe symptoms manifesting and arising from various skin diseases andmaladies. Most especially, therapeutic agents and actives that willrepair, rejuvenate, strengthen and/or mitigate damage to the skin, mostespecially to the strength, integrity and/or performance of the skinbarrier and its function.

Additionally, there is a continuing need to identify therapeutic agentsand actives that will enhance and/or hasten the repair of the epidermisfollowing injury, whether due to a skin malady, trauma, environmentalexposure and attack, etc.

There is an urgent need to identify therapeutic agents and activeshaving the properties and performance as recited above, which are simpleand cost effective and do not require extensive extraction and isolationtechniques as found with protein based therapies.

Finally, there is a need to identify therapeutic agents and actives thathave broad spectrum applications, especially those that are capable ofaddressing the fundamental defects and maladies in the keratinocytedifferentiation process and in the development of the barrier andstratum corneum.

SUMMARY OF THE INVENTION

According to the present teaching there are provided novel esters ofisosorbide that are found to improve and/or address defects orimbalances in keratinocyte differentiation, improve and/or repair skinbarrier building and defense of its function and integrity as well asimprove overall stratum corneum development, structure and architecture.Specifically, it has now been found that certain esters of isosorbideare capable of modifying, recalibrating and/or regulating the expressionof genes, genetic networks, and cellular pathways in mammalian skin forimproving and/or repairing the epidermis and its function as well as inaddressing, combating, mitigating and/or preventing the manifestation ofdisease conditions associated with certain diseases and defects orimbalances in the skin.

In accordance with one aspect of the present disclosure there areprovided novel isohexide compounds, especially isosorbide compounds,having the Structure 1:

wherein R₁ and R₂, which may be the same or different, are independentlyselected from C₁₅ to C₁₉ saturated or unsaturated n-alkyl carboxylategroups, provided that when R₁ and R₂ are different, one of R₁ or R₂ mayalso be hydrogen. Preferably, R₁ and R₂ or at least one of R₁ and R₂ aremono-unsaturated and/or polyunsaturated n-alkyl carboxylate groups offrom 15 to 19 carbon atoms, more preferably polyunsaturated n-alkylcarboxylate groups of 15 to 19 carbon atoms, most preferably apolyunsaturated n-alkyl carboxylate group wherein R₁=R₂₌₁₇ carbon atoms.Additionally, the isohexide element is preferably and predominantly theisosorbide, preferably at least 50 mole %, more preferably at least 70mole %, most preferably at least 90 mole % isosorbide.

In accordance with a second aspect of the present invention there areprovided novel isohexide ester compositions, particularly novelisosorbide ester compositions, comprising a mixture of two or moreisohexide esters, all of which may be in accordance with Structure 1 orwherein at least 50%, preferably at least 70%, by weight of theisohexide mixture comprises isohexides according to Structure 1 wherein,once again, R₁ and R₂, which may be the same or different, areindependently selected from C₁₅ to C₁₉ saturated or unsaturated n-alkylcarboxylate groups, provided that when R₁ and R₂ are different, one ofR₁ or R₂ may also be hydrogen. Preferably, R₁ and R₂ or at least one ofR₁ and R₂ are mono-unsaturated and/or polyunsaturated n-alkylcarboxylate groups of from 15 to 19 carbon atoms, more preferablypolyunsaturated n-alkyl groups of 17 to 19 carbon atoms, most preferablya polyunsaturated n-alkyl carboxylate group of 17 carbon atoms. Themixtures according to this aspect of the present teaching may bemixtures of mono- and di-esters of the same isohexide and the samen-alky carboxylate groups, mixtures of mono- and di-esters of the sameisohexide and different n-alky carboxylate groups, and mixtures of mono-and/or di-esters of different isohexides and the same or differentn-alkyl carboxylate groups. The preferred isohexides are theisosorbides, especially those compounds and mixtures of such compoundswherein at least 50 mole %, preferably at least 70 mole %, mostpreferably at least 90 mole % is the isosorbide ester. Additionally, asnoted, the mixture may comprise one or more of the aforementionedisohexide compounds of Structure 1 in combination with one or moreisohexide not according to Structure 1, i.e., wherein the ester groupsare other than as specified for Structure 1. Where isohexide estersother than those according to Structure 1 are present, at least 50% byweight, preferably at least 70% by weight, of isohexide estercomposition is isohexide esters according to Structure 1. In thepreferred embodiment of the isohexide ester composition, the isohexideester composition consists essentially of isohexides wherein at least 50mole %, more preferably at least 70 mole %, of the isohexide mixture isa single isohexide according to Structure 1.

According to a third aspect of the present disclosure there are providedisohexide ester compositions which are the reaction product of one ormore isohexides, preferably isosorbide, and one or more long chain fattyacid or the triglyceride precursor therefore, wherein at least 50%,preferably at least 70%, by weight long chain fatty acids have from 16to 20 carbon atoms, preferably from 18 to 20 carbon atoms, mostpreferably 18 carbon atoms. The long chain fatty acids may be saturated,mono-unsaturated and/or poly-unsaturated, preferably mono-unsaturatedand/or poly-unsaturated, most preferably polyunsaturated. Preferably thelong chain fatty acid reactant is a natural oil, more preferably apurified natural oil, having the requisite long chain fatty acids and/orprecursor triglyceride(s). As above, the resulting isohexides may be themono- or di-esters or combinations thereof. Furthermore, it is preferredthat the isohexide esters are at least 50 mole %, more preferably atleast 70 mole %, most preferably at least 90 mole the isosorbide esters.In its most preferred embodiment of this aspect of the presentinvention, the resulting isohexide ester composition consistsessentially of the aforementioned long chain fatty acid esters ofisosorbide with minimal, if any, of the other isohexide isomers, mostespecially the di-esters.

In accordance with a fourth aspect of the present disclosure, there areprovided advanced skin care products which ameliorate, reduce andreverse the effects and/or manifestation of skin aging, particularlythrough modulation of SASPase and FLG. Specifically, it has now beenfound that topical application of an effective amount of one or morecompounds having the Structure 1 to the skin results in a markedimprovement in barrier function, appearance and health, especially asmanifested in a reduction in the number and/or degree (severity) of finelines and wrinkles.

In accordance with another aspect of the present disclosure, there areprovided pharmaceutical and/or health and beauty compositions containingan effective amount of at least one compound having Structure 1 abovethat are capable of modulating granular layer-expressing genes so as toincrease certain proteins associated with skin maintenance as well asother important biological functions and processes in the human body foroverall improved health.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of modulating skin aspartic proteases (SASPase) andfilaggrin to reinforce the skin barrier function and to stimulateepidermal regeneration and differentiation.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of modulating at least one or more barrier building genes,namely, Involucrin (IVL), Keratinocyte proline-rich protein (KPRP),Cornulin (CRNN), Corneodesmosin (CDSN), Dehydrogenase 9 (DHRS9) andwould be expected to increase expression of corresponding proteins whichhelp build/strengthen the barrier of skin.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of modulating one or more barrier building genes related tolipids, such as, SMPD (Sphingomyelin phosphodiesterase), GBA(Glucocereobrosidase/Glucosyl ceramidase), ABC (ATP-binding cassette),DHCR (24-dehydrcholesterol reductase), ELOV (Elongation of very longchain fatty acids) and would be expected to increase expression ofcorresponding lipids which help build/strengthen the barrier of skin.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of modulating one or more genes related to lipids so as toincrease skin lipid levels, specifically, ceramide levels, to achievesignificant improvements in the appearance or manifestation of at leastone sign of aging.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of modulating one or more late cornified envelope (LCE)genes and would be expected to increase the expression of proteins whichhelp strengthen the barrier of skin.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of defending skin against inflammation-induced onslaught.

In yet another embodiment of the present invention, there are providedpharmaceutical and/or health and beauty compositions containing aneffective amount of at least one compound having Structure 1 above thatare capable of enhancing keratinocyte differentiation and/or developmentof the stratum corneum so as to enhance skin recovery following traumaor injury to the skin.

In yet another embodiment of the present invention there are providemethods for accomplishing the above-referenced effects comprisingapplying an effective amount of at least one compound according toStructure 1 to the skin or area of skin to be treated.

The compounds described in Structure 1 may be applied as is, or in asuitable carrier, particularly a dermatologically acceptable carrier orformulation. Most preferably, these compounds are formulated as part ofa skin care product having at least one other active ingredient for skincare and/or treatment products.

Finally, while each of the aforementioned embodiments pertaining to theend-use of the compounds of Structure 1 refer to the use of one or moreof such compounds, it is preferred that the one or more isohexide esterbe the mixture of such isohexide esters resulting from the reaction ofan isohexide or mixture of isohexides, most preferably isosorbide, andfatty acids obtained from a natural oil, preferably a purified naturaloil, having at least 50%, preferably at least 70%, by weight of longchain fatty acid (fatty acid ester groups in the case of thetriglycerides) of 16 to 20, preferably 18 to 20, most preferably 18,carbon atoms. Most preferably, at least 50%, more preferably, at least70% of the long chain fatty acid ester groups are the same. Furthermore,it is preferred that at least 50 mole %, more preferably at least 70mole %, most preferably at least 90 mole % of the isohexide esters arethe isosorbide esters.

DETAIL DESCRIPTION OF THE DRAWINGS

FIG. 1 presents a series of photomicrographs (a) thru (d) of skinsamples depicting the impact of cytokine treatment and therestorative/protective effect of the isohexide esters of the presentteachings.

DETAIL DESCRIPTION OF THE INVENTION

Although the specification when referencing end-use applications for thenovel isohexides is primary focused on and recites skin andepidermis/epidermal care and treatment, it is to be appreciated that thepresent teachings also extend to the care and treatment of certainelements of the mucosa, especially the nose and mouth, most especiallythe lips. Furthermore, while the specification teaches of theapplication and performance of the present invention in terms of certainspecific embodiments, it is to be understood that the present disclosureis to be considered as an exemplification of the principles of theinvention and is not intended to limit the invention to the embodimentsillustrated. Finally, as used herein and in the appended claims, it isto be understood that the term “n-alky carboxylate” means ann-hydrocarbyl carbonyl moiety, which may be saturated or unsaturated,unless otherwise specified, and the carbon number when referencing thesize of the n-alkyl carboxylate groups refers only to the long chainn-hydrocarbyl portion of the carboxylate and does not include thecarboxylate carbon atom itself: hence, when the n-alkyl group is C17,the carboxylate may be the stearate group, the oleate group, thelineolate group, etc.

The present invention is based upon the unexpected finding that certainhigher (di)alkyl esters of isohexide, i.e., those wherein the alkylester group(s) have a C₁₆ to C₂₀ chain length, have a marked effect inmodulating epidermal expressing genes, especially granular-layerexpressing genes, in ways that improve epidermal development, structure,and integrity as well as function and, thereby, provide therapeuticrelief and treatment for a number of skin diseases manifesting inadverse function and development of the epidermis. Though not limitedthereto, these compounds have a marked beneficial impact on, among otherproteins, SASPase and filaggrin. While not intending to be bound bytheory or mechanisms, it is believed that these compounds are capable ofup-regulating key epidermal differentiation genes/proteins therebyproviding many of the desired attributes that are required for, amongothers, normal epidermal barrier function and formation, management ofwater content, skin elasticity and barrier function recovery,rejuvenation and repair of skin trauma and injury, etc., all of whichenable and manifest improved skin health and appearance and reversal ofthe effects of various skin diseases.

Dianhydrohexitols are well documented by-products of the starch industryobtained by dehydration of D-hexitols, which are made by a simplereduction of hexose sugars. About 650,000 tons of dianhydrohexitols areproduced annually worldwide. These chiral biomass-derived products existas three main isomers (isosorbide (2), isomannide (3), and isoidide (4),depending on the configuration of the two hydroxyl functions (derivedfrom D-glucose, D-mannose, and L-fructose, respectively). Isosorbide,which is produced from glucose via sorbitol, is the most widelyavailable dianhydrohexitol.

These three compounds, as well as the lower (C₁-C₁₀) mono- and di-alkylesters and ethers thereof, and the mono and di-nitrates thereof, arewell known and already used in various medical, pharmaceutical andhealth and beauty applications. The un-substituted and lower alkyl estersubstituted isohexides are very soluble in water and biologicallyharmless. The lower alkyl ethers and the unsubstituted compounds havebeen used as carriers in a number of skin care products to aid in thetransport of other active ingredients through the skin membrane. Thelower alkyl ethers have also found utility in dentifrices, aiding in theremoval of plaque due to their osmotic properties. Isosorbide dinitrateand isosorbide mononitrate have been used to treat angina pectoris. Likeother nitric oxide donors, these drugs lower portal pressure byvasodilation and decreasing cardiac output.

The novel isohexide compounds according to the present disclosure havethe Structure 1:

wherein R₁ and R₂, which may be the same or different, are independentlyselected from C₁₅ to C₁₉ saturated or unsaturated n-alkyl carboxylategroups, provided that when R₁ and R₂ are different, one of R₁ or R₂ mayalso be hydrogen. Preferably, R₁ and R₂ or at least one of R₁ and R₂ aremono-unsaturated and/or polyunsaturated n-alkyl carboxylate groups offrom 15 to 19 carbon atoms, more preferably polyunsaturated n-alkylcarboxylate groups of 15 to 17 carbon atoms, most preferably apolyunsaturated n-alkyl carboxylate group of 17 carbon atoms.

The mono- and di-alkylesters of isohexide of the present invention maybe formed by any of the known methods for the esterification of theisohexides or by modified versions of those methods, as will be apparentto those skilled in the art having the benefit of this disclosure. Forexample, they may be prepared by nucleophilic acyl substitution wherethe carbonyl compound is used as an electrophile and is attacked by anucleophilic alcohol, such as the isohexides in the present invention.Alternatively, one may employ a carboxylate anion as a nucleophile thatdisplaces a halide ion in an SN2 reaction: essentially, esterificationby alkylation reverses the roles of “classic” carbonyl chemistry.Suitable methods are described in, e.g., P. Stoss and R. Hemmer,“1,4:3,6-Dianhydrohexitols”, in Advances in Carbohydrate Chemistry andBiochemistry, Vol. 49, pp. 93-173 (1991), Z. Cekovic and Z. Tokic,Synthesis, pp. 610-612 (1989); Courtalds Ltd. NL 6,405,497 (1962) andChem. Abstr., 69 (1968) 67,666, all of which are hereby incorporatedherein by reference in their entirety.

Typically, the isohexide mono- and di-alkyl esters prepared according tothese processes will comprise a mixture of isohexides. In this instance,the mixture arises simply because of the difficulty in purifying theisohexide starting material. For example, preparations of isosorbidedilinoleate (IDL), even with substantially pure linoleic acid, arelikely to contain dilinoleate isomannide and dilinoleate isoidide aswell as small amounts of the monolinoleate equivalents. One can isolateor purify the desired esterified isohexide by various purification anddistillation techniques known to those skilled in the art. Even so, itis to be realized that essentially pure products are likely to have asmall percentage, perhaps 1-2% by weight of each of the otherdi-substituted isomers as well as 1-2% by weight of the mono-substitutedequivalents.

In following the present teachings also pertain to mixtures ofisohexides according to Structure 1. In this instance, the mixturesconsist essentially of mono- and di-esters of the same isohexide and thesame n-alky ester group, mixtures of mono- and/or di-esters of the sameisohexide and different n-alky ester groups, mixtures of mono- and/ordi-esters of different isohexides and the same n-alkyl ester group, andmixtures of mono- and/or di-esters or different isohexides and differentn-alkyl ester groups. The make-up of the specific isohexide estercomposition depends upon the selection of the isohexide startingmaterials, the selection of the starting fatty acids and/or fatty acidprecursor triglyceride and the mole ratio of the two as well as thereaction time. In this respect, a low mole ratio of fatty acid toisohexide will result in mono- or predominantly mono-esters. Higher moleratios will result in more di- or predominantly di-, if not wholly di-,esters: though shortened reaction times may shift the resultant estersback to the mono- or mixture of mono- and di-esters. Similarly,selection of the starting isohexide materials also affects the make-upof the resultant isohexide composition. As noted above, isohexides aretypically of three different isomers, depending upon the relativeconcentration of the three isomers one may form more of one isomer thanthe other. The preferred isohexides are the isosorbides, especiallythose compounds and mixtures of such compounds wherein at least 50 mole%, preferably at least 70 mole %, most preferably at least 90 mole % isthe isosorbide ester. Similarly, the preferred isohexide esters arethose wherein at least 40 mole %, preferably at least 50 mole %, mostpreferably at least 70 mole % of the ester groups are the same, and aremost preferably the linoleic ester group.

It is also to be appreciated that the present teaching also applies tomixtures of any of the aforementioned isohexide compounds and mixturesof isohexide compounds in combination with or further combination withone or more isohexide mono- and/or di-esters corresponding to Structure5

wherein the carbon numbers for the ester groups R₄ and R₅ are outside ofthe ranges for R₁ and R₂ above, especially those esters wherein theester groups R₄ and R₅ have from 1 to 10 carbon atoms, most especially 1to 9 carbon atoms: the carbon number referring to the carbon atomsexcluding the carboxylate carbon atom. Exemplary other isohexide estersare well known and are described in, among others U.S. Pat. No.8,496,917. Specific other isohexide esters include isosorbidemono-caprylate, isosorbide dicaprylate, isosorbide mono-methylfumarateand isosorbide di-methylfumarate. In this embodiment the isohexides ofthe instant application, i.e., those according to Structure 1 above,comprise at least 50 weight %, more preferably at least 70 weight %,most preferably at least 90 weight % of the isohexide mixture. Ofcourse, such other isohexide esters are not required and, indeed, it maybe desirable to exclude such other isohexides, including, specificallythe exclusion of any or all of isosorbide mono-caprylate, isosorbidedicaprylate, isosorbide mono-methylfumarate and isosorbidedi-methylfumarate.

While the present teachings apply to the isohexide esters in theirpurified or isolated from or as mixtures of their isomeric equivalents,it is more typical that the isohexide esters are mixtures of different,not merely isomeric equivalent, isohexide esters. Specifically, as notedabove, the isohexide esters according to Structure 1 may be formed byreacting the desired long chain fatty acid or precursor, e.g., thetriglyceride form which the fatty acid is derived, with the isohexide,especially isosorbide, or a dianhydrohexitol mixture, particularly anisohexide mixture, containing isosorbide; however, it is more typical toemploy fatty acid oils obtained or derived from natural sources.Suitable oils include those disclosed in Orsavova, J. et. al., “FattyAcids Composition of Vegetable Oils and Its Contribution to DietaryEnergy Intake and Dependence of Cardiovascular Mortality on DietaryIntake of Fatty Acids,” Int. J. Mol. Sci. 2015, 16, 12871-12890, whichis incorporated herein by reference, especially the oils isolated fromsafflower, grape seed, Silybum marianum, hemp, sunflower, wheat germ,pumpkin seed, sesame, rice bran, almond, rapeseed, peanut, olive, andcoconut. Table 1 presents the breakdown of the oleic acid, linoleic acidand linolenic acid content (% by weight) of some of the more preferredoils.

TABLE 1 Oils Oleic acid Linoleic acid Linolenic acid Safflower  8-2168-83 <0.5 Grapeseed 16.2 70.6 Rosehip ~14 ~44 ~34 Sunflower 14-40 48-74~0.4 Hemp ~10 ~52 ~10 Walnut 21 56 13 Sesame ~39 ~46 Evening Primrose ~850-72 7-10 Soybean 17-30 48-58 5-11 Wheat-germ 12-23 52-59 3-10

These oils are comprised of a plurality of different fatty acids,oftentimes a combination of unsaturated, mono-saturated and/orpolyunsaturated long chain fatty acids. Accordingly, the isohexideesters derived therefrom also comprise a combination of the same fattyacid esters. Those isohexide ester compositions pertinent to the instantinvention comprise a mixture of two or more isohexide esters wherein atleast 50%, preferably at least 70%, by weight of the isohexide mixturecomprises isohexides according to Structure 1 wherein, once again, R₁and R₂, which may be the same or different, are independently selectedfrom C₁₅ to C₁₉ saturated or unsaturated n-alkyl carboxylate groups,provided that when R₁ and R₂ are different, one of R₁ or R₂ may also behydrogen. Preferably, R₁ and R₂ or at least one of R₁ and R₂ aremono-unsaturated and/or polyunsaturated n-alkyl carboxylate groups offrom 15 to 19 carbon atoms, more preferably polyunsaturated n-alkylcarboxylate groups of 17 to 19 carbon atoms, most preferably apolyunsaturated n-alkyl carboxylate group of 17 carbon atoms.Preferably, the isohexide ester composition consists essentially ofisohexides according to Structure 1, more preferably, at least 50%,preferably at least 70%, by weight of the isohexide mixture is a singleisohexide according to Structure 1. The reference to consistingessentially of recognizes the fact that there may be and, most likelyare, small insignificant or even trace amounts of other esters presentowing to the presence of the corresponding fatty acids in the startingmaterials. Similarly, as noted above, depending upon thedianhydrohexitol starting material, the isohexide ester compositions maycomprise the isomeric equivalents of each of the isohexide esters in thecomposition as well. In its most preferred embodiment the isohexides arethe isosorbides with minimal, if any, of the other isohexide isomerspresent. Even then it may be impossible to eliminate all isomers. In anyevent, it is preferred that the isohexides are the isosorbides,especially those mixtures of isohexides wherein at least 50 mole %,preferably at least 70 mole %, most preferably at least 90 mole % of theisohexides are the isosorbide esters.

The isohexide ester compositions of the present teaching are formedaccording to the same processes as described above with respect to theindividual isohexide esters except that the natural oils, preferably thepurified oils, containing the requisite fatty acids and/or theirtriglyceride precursors are used as the fatty acid source startingmaterial as opposed isolating and/or purifying the specific fatty acidto be used.

As indicated, the isohexide mono- and di-alkyl esters may be used intheir purified forms or as the isomer mixtures or as mixtures ofmultiple isohexide mono- and/or di-alkyl esters and/or, as appropriate,their respective isomeric equivalents. However, it is also to beappreciated that any of the foregoing may be used alone or incombination or further combination with one or more mono- and/ordi-alkanoyl isohexides having similar structures to that of Structure 1but wherein the carbon number of the alky ester groups are from 1 to 14,preferably from 6 to 10. For simplicity of discussion and to avoidrepetitiveness, henceforth the term alkanoyl isohexides shall be deemedto refer, in general, to the monoalkanoyl- and/or dialkanoyl-isohexidesof Structure 1 above as well as the aforementioned isohexide estercompositions comprising monoalkanoyl- and/or dialkanoyl-isohexides ofStructure 1 as well as the mixtures of the foregoing with monoalkanoyl-and/or dialkanoyl-isohexides that fail to meet the limitations ofStructure 1, provided that at least 50%, preferably at least 70%, byweight of the said monoalkanoyl- and/or dialkanoyl-isohexides are inaccordance with Structure 1. Where it is stated that certain propertiesand/or functions have been found, it means that at least one member ofthe foregoing class has been found to show or manifest the specifiedproperty or characteristic unless otherwise indicated: though it isbelieved that the properties and characteristics are common to eachclass member.

Where a mixture of isohexide esters is present, it is preferred that allof the isohexide esters be according to the Structure 1. The preferredisohexides are the isosorbides, especially those compounds and mixturesof such compounds wherein at least 50 mole %, preferably at least 70mole %, most preferably at least 90 mole % is the isosorbide ester.Additionally, as noted, the mixture may comprise one or more of theaforementioned isohexide compounds of Structure 1 in combination withone or more isohexide not according to Structure 1. In this embodimentit is preferred that the isohexides are at least 50 mole %, morepreferably at least 70 mole %, most preferably at least 90 mole %isosorbides. Indeed, in its most preferred embodiment the isohexides arethe isosorbides with minimal, if any, of the other isohexide isomerspresent. Even then it may be impossible to eliminate all isomers.

The alkanoyl isohexide compounds and/or mixtures thereof may be used asis or may be formulated with an appropriate carrier or solvent and/orinto a skin care/treatment composition. Preferably, the alkanoylisohexides are formulated into or combined with a dermatologicallyacceptable carrier or into a skin care/treatment composition. Mostpreferably, the alkanoyl isohexide comprises a component of a skin careformulation or product having multiple active components for protectingand/or rejuvenating skin.

In addition to the manifestation of physical improvement in skinappearance and health, the alkanoyl isohexides have also been found tomanifest a gene modulation effect. The Gene Ontology analysis showsmultiple types of skin-relevant responses elicited by the alkanoylisohexides of the present invention. For example, isosorbide dilinoleate(IDL), particularly that obtained by esterifying isosorbide with fattyacids obtained from sunflower oil, has demonstrated an overallstimulatory effect on epidermis morphogenesis, through the stimulationof proliferation, migration and differentiation of keratinocytes,accompanied by an increase in angiogenesis. It is interesting to notethat this epidermis-stimulatory effect has been observed against agenerally conservative background of suppressed gene expression andsignal transduction. This data points to the specificity of thestimulatory effect of IDL towards the skin tissue, while maintaining theoverall systemic homeostasis. Additionally, exposure to IDL resulted inan activation of some selective components of the immune response,without translation into a chronic inflammatory response. Finally, IDLhas shown effects on the genes commonly considered important forimproving hydration of the dermis and epidermis, regulating bothepidermal differentiation and lipid synthesis/secretion, which in turninfluence permeability barrier homeostasis.

The compositions for improving or maintaining skin health and appearanceaccording to the present invention will typically comprise one or moreof the specified alkanoyl isohexides, oftentimes a combination ofalkanoyl isohexides, in an amount of from about 0.01 to about 100 wt %,preferably from about 0.5 to about 30 wt %, more preferably from about0.5 to about 20 wt %, most preferably from about 1.0 to about 10 wt %,based on the total weight of the skin care composition. From a practicalstandpoint, these compositions will comprise the one or more alkanoylisohexide(s) in a dermatologically acceptable carrier. Additionally,these compositions may optionally include an effective amount of one ormore skin protective and/or treatment ingredients such as antioxidants,sunscreens, vitamins, anti-inflammatory agents, self-tanning agents,moisturizers, emollients, humectants, compatible solutes and the like,and mixtures thereof, in their conventional amounts.

The skin care compositions according to the present invention aregenerally applied topically and may take the form of a liquid, lotion,crème, serum, spray, ointment, gel, foam, liquid foundation, or balm andmay be presented as a cosmetic or make-up product, antiperspirant, oranother topically applicable health and beauty aid and/orpharmacological product. These types and forms of skin care compositionsmay themselves be in the form of emulsions, dispersions, liposomes,coacervates and the like. The skin care compositions may also take theform of various articles such as pads, swabs, wipes, sponges, and thelike that are saturated with or otherwise contain or hold the actualskin care composition but which release the same or leave a film of thesame when swiped across the skin surface.

The term “dermatologically acceptable carriers” refers to vehicles,diluents, and carriers known for use in dermatological compositions.These carriers are materials or combinations of materials that are usedto deliver the active components, here the alkanoyl isohexide(s), to thedesired application site, typically the skin. Preferred dermatologicallyacceptable carriers are carrier materials or compositions that aresuitable for application, especially long term and repeated application,to the skin without manifesting sensitization or irritation. Generallyspeaking, the dermatologically acceptable carrier will comprise fromabout 0.1 to about 99.9% by weight of the inventive skin carecompositions.

Suitable dermatologically acceptable carriers include any of the knowntopical excipients and like agents necessary for achieving theparticular form of the skin care composition desired. Exemplaryexcipients include, e.g., mineral oils and emulsifying agents as well aswater, alcohol, or water/alcohol combinations, or other solvent(s) orsolvent systems in which the aforementioned actives may be, e.g.,soluble, dispersed, emulsified, etc. Preferably, though, the skin carecompositions will include excipients and the like that create asubstantially stable, homogenous composition and/or provide body andviscosity to the composition so that the actives do not merely run offthe skin once applied.

The specific choice of carrier or carrier ingredients will depend uponthe delivery method itself as well as the speed with which the activeingredients, e.g., the alkanoyl isohexide(s), are to come in contactwith or penetrate the application site. For example, an oil basedcarrier will remain on the skin for a relatively long period of time,allowing for a slow transfer of the active to the skin; whereas analcohol solvent, because of its volatility, will flash off quitequickly, leaving the actives on the skin in a matter of seconds or so.Still, other solvents, like DMSO and, especially, DMI (dimethylisosorbide), will help speed up the penetration of the actives into theskin.

Generally speaking, any known carrier or base composition employed intraditional skin care/treatment compositions may be used in the practiceof the present invention. Suitable carriers and carrier compositions aredescribed at length in, for example, Gonzalez et. al.—U.S. Pat. No.7,186,404; Aust et. al.—U.S. Pat. No. 7,175,834; Roseaver et. al.—U.S.Pat. No. 7,172,754; Simoulidis et. al.—U.S. Pat. No. 7,175,835; Mongiatet. al.—U.S. Pat. No. 7,101,536; Maniscalco—U.S. Pat. No. 7,078,022;Forestier et. al. U.S. Pat. Nos. 5,175,340, 5,567,418, 5,538,716, and5,951,968; Deflandre et. al.—U.S. Pat. No. 5,670,140; Chaudhuri—U.S.Pat. Nos. 6,831,191, 6,602,515, 7,166,273, 6,936,735, and 6,699,463;Chaudhuri et. al.—U.S. Pat. Nos. 6,165,450 and 7,150,876; Bonda et. al.U.S. Pat. No. 6,962,692; and Wang et. al. U.S. Pat. No. 5,830,441, allof which are incorporated herein by reference in their entirety. Thoseskilled in the art will readily recognize and appreciate what carriersmay be employed in light of the intended form and/or delivery method forthe inventive sunscreen compositions.

Though a carrier by itself is sufficient, the inventive compositions ofthe present invention may, and preferably will, contain various othercomponents typically associated with skin care/treatment products. Forexample, various skin care agents including, but not limited to,conventional skin care excipients as well as additional photoprotectiveagents and skin lightening agents may be present. Such agents include,but are not limited to antioxidants, sunscreens, skin lighteningactives, exfoliants, anti-acne actives, vitamins, anti-inflammatoryagents, self-tanning agents, moisturizers, compatible solutes,humectants, emollients and the like, and mixtures thereof, in theirconventional amounts. Exemplary agents and additive materials aredescribed briefly below as well as in the aforementioned patents,especially Maniscalco—U.S. Pat. No. 7,078,022. Each of these will bepresent in their conventional amount, though, as noted above and in thefollowing examples, certain of these additives will manifest a synergywith the isohexides of the present application whereby the sameperformance may be realized with lesser amounts. In any event, suchingredients will typically be present in an amount of 1 to 30 wt %,preferably 2 to 20 wt %; though again, highly active ingredients, likethe sunscreen actives, antioxidants, and anti-inflammatory agents may beeffective at levels as low as 0.01 wt %, preferably 0.1 wt %. This isespecially true for highly active agents like the meroterpenes,especially the purified versions, most especially purified bakuchiol.

Suitable antioxidants include, but are not limited to, water-solubleantioxidants such as sulfhydryl compounds and their derivatives (e.g.,sodium metabisulfite and N-acetyl-cysteine), lipoic acid anddihydrolipoic acid, resveratrol, lactoferrin, and ascorbic acid andascorbic acid derivatives (e.g., ascorbyl palmitate and ascorbylpolypeptide). Oil-soluble antioxidants suitable for use in thecompositions of this invention include, but are not limited to,butylated hydroxytoluene, retinoids (e.g., retinol and retinylpalmitate), tocopherols (e.g., tocopherol acetate), tocotrienols,alkylresorcinols, meroterpenes, curcurmin and its derivatives andubiquinone. Natural extracts containing antioxidants suitable for use inthe compositions of this invention, include, but not limited to,extracts containing flavonoids and isoflavonoids and their derivatives(e.g., genistein and diadzein), extracts containing resveratrol and thelike. Examples of such natural extracts include grape seed, green tea,pine bark, Phyllanthus emblica, Terminalia chebula, Terminalia belerica,Phyllanthus amarus, and meroterpenes, such as, Bakuchiol (available fromSytheon Ltd under the trade name Sytenol® A) or other meroterpenes,Other examples of antioxidants may be found on pages 1612-13 of the ICIHandbook and in Ghosal—U.S. Pat. No. 6,124,268 as well as, preferably,Chaudhuri (U.S. Pat. Nos. 8,414,870 and 8,617,528), all of which areincorporated herein by reference in their entirety.

Sunscreen actives are of two types, inorganic actives that work byreflecting the UV light and organic actives that work, predominately, byabsorbing UV energy. The amount of the sunscreen active to beincorporated into the sunscreen formulations is that which isconventional in the art. Typically, the amount is dependent upon, amongother factors, the delivery means, e.g., it is applied as a spray orlotion; the stability of the active; the efficacy of the selectedsunscreen active itself; and the application rate, as well as theparticular SPF desired. From the commercial perspective, another factorinfluencing the level of such sunscreen actives in the sunscreenformulations is the regulatory limitations on their use. In the UnitedStates, for example, strict controls are placed upon the maximum levelat which approved sunscreen actives may be present. Similarregulatory/governmental controls may also dictate which sunscreenactives may be used and at what amount in other countries as well.

Suitable organic sunscreen actives include, for example, avobenzone(butyl methoxydibenzoylmethane), cinoxate, benzophenone-8, dioxybenzone,homosalate, octylsalate, menthyl anthranilate, octocrylene, ethyhexylmethoxycinnamate, n-octyl methoxycinnamate, octyl salicylate,oxybenzone, padimate 0, ethylhexyl salicylate, benzophenone-3,p-aminobenzoic acid (PABA), ethylhexyl dimethyl PABA, glyceryl PABA,phenylbenzimidazole sulfonic acid, sulfisobezone, trolamine salicylate,4-methylbenzylidene camphor, bisoctrizole, bemotrizinol, ecamsule,drometrizole trisiloxane, disodium phenyl dibenzimidazoletetrasulfonate, diethylamino hydroxybenzoyl hexyl bezoate, octyltriazone, benzophenone-4, ethyhexyl triazone, diethylhexyl butamidotriazone, bisimidazylate, polysilicone-15, etc.

Inorganic sunscreens include, but are not limited to, microfine surfacetreated titanium dioxide and microfine untreated and surface treatedzinc oxide. The titanium dioxide in the sunscreen compositionspreferably has a mean primary particle size of between 5 and 150 nm,preferably between 10 and 100 nm. Titanium oxide may have an anatase,rutile, or amorphous structure. The zinc oxide in the sunscreencompositions preferably has a mean primary particle size of between 5 nmand 150 nm, preferably between 10 nm and 100 nm. Examples of suitablehydrophobically modified titanium dioxide compositions include but arenot limited to the following:

-   -   UV Titans® X161, M160, M262 (surface treated with stearic acid        and alumina) (Kemira)    -   Eusolex® T-2000 (surface treated with alumina and simethicone)        (Merck KGaA)    -   T-Cote® (surface treated with dimethicone) (BASF)    -   Mirasun® TiW60 (surface treated with silica and alumina)        (Rhodia)    -   Tayaca MT100T (surface treated with aluminum stearate) (Tayaca)    -   Tayaca MT-100SA (surface treated with silica and alumina)        (Tayaca)    -   Tayaca MT-500SA (surface treated with silica and alumina)        (Tayaca)    -   Tioveil® EUT, FIN, FLO, FPT, GCM, GPT, IPM, MOTG, OP, TG, TGOP        (surface treated with silica and alumina, 40% dispersion in a        range of cosmetic vehicle) (ICI)    -   Eusolex® T-45D (surface treated with alumina and simethicone,        45% dispersion in isononoylnonaoate) (Merck KGaA)    -   Eusolex® T-Aqua (surface treated with aluminum hydroxide, 25%        dispersion in water) (Merck KGaA)    -   Examples of suitable untreated and hydrophobically modified zinc        oxide include but are not limited to the following:    -   Z-Cote® (uncoated microfine zinc oxide) (BASF)    -   Z-Cote® HP-1 (surface treated with dimethicone) (BASF)    -   Sachtotec® LA 10 (surface treated with lauric acid) (Sachtleben)    -   Sachtotec® (uncoated microfine zinc oxide) (Sachtleben)    -   Spectraveil® FIN, IPM, MOTG, OP, TG, TGOP (uncoated, 60%        dispersion in a range of cosmetic vehicle) (ICI)    -   Z-sperse® TN (untreated, dispersion in C12-15 alkyl benzoate)        (Collaborative)    -   Z-sperse® TN (untreated, dispersion in octydodecyl        neopentanoate) (Collaborative)

Most preferably, if present, the skin care compositions of the presentinvention will comprise a combination of such sunscreen actives. In thisrespect, it is well known that certain sunscreen actives have betterstability, hence longevity, than others; while others have betterabsorptive capabilities, whether in reference to selectivity for certainUV energy of certain wavelength(s) or cumulative absorptivecapabilities. Hence, by using combinations of such UV sunscreen actives,one is able to provide greater protection. Suitable combinations arewell known in the art and within the skill of a typical artisan in thefield.

Some sunscreens, such as avobenzone, are not photchemically stable.Therefore, it may be and is desirable to include appropriate stabilizersfor improvement in sun protection. Suitable photostabilzers include, butare not limited to the following examples—Oxynex® ST (Diethylhexylsyringylidenemalonate, EMD Chemicals), RonaCare® AP (Bis-EthylhexylHydroxydimethoxy Benzylmalonate, EMD Chemicals), Polycrylene®(Polyester-8, Hallstar), Solastay™ S₁ (Ethylhexyl methoxycrylene,Hallstar), Corapan® TQ (Diethylhexyl napthalate, Symrise), Octocrylene,Trimethoxybenzylidene Pentanedione (Synoxyl® HSS—Sytheon Ltd.) orcombinations thereof.

The skin care compositions of the present invention may also include oneor more vitamins and/or their derivatives. Vitamins and vitaminderivatives include, for example, vitamin A, vitamin A propionate,vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiaminechloride hydrochloride (vitamin B.sub.1), riboflavin (vitamin B.sub.2),nicotinamide, vitamin C and derivatives (for example ascorbyl palmitate,magnesium ascorbyl phosphate, ascorbyl acetate), vitamin D,ergocalciferol (vitamin D.sub.2), vitamin E, DL-.alpha.-tocopherol,tocopherol E acetate, tocopherol hydrogensuccinate, vitamin K.sub.1,esculin (vitamin P active ingredient), thiamine (vitamin B₁), nicotinicacid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin B₆),pantothenic acid, biotin, folic acid and cobalamine (vitamin B₁₂).Preferred vitamins are, for example, vitamin A palmitate, vitamin C andderivatives thereof, DL-α-tocopherol, tocopherol E acetate, nicotinicacid, pantothenic acid and biotin. Vitamin E, which is often added tocosmetic and personal care products is also preferably stabilized by thecompounds according to the invention. Additional preferred vitamins areVitamin C and K and derivatives thereof.

The compositions of the present invention may also include one or moreamino acids and their derivatives. Amino acids and their derivativesinclude, for example, essential and non-essential amino acids and theirderivatives. Eight amino acids are generally regarded as essential forhumans: phenylalanine, valine, threonine, tryptophan, isoleucine,methionine, leucine, and lysine. Additionally, cysteine (orsulphur-containing amino acids), tyrosine (or aromatic amino acids),histidine and arginine are required by infants and growing children.Essential amino acids are so called not because they are more importantto life than the others, but because the body does not synthesize them,making it essential to include them in one's diet in order to obtainthem. In addition, the amino acids arginine, cysteine, glycine,glutamine, histidine, proline, serine and tyrosine are consideredconditionally essential, meaning they are not normally required in thediet, but must be supplied exogenously to specific populations that donot synthesize it in adequate amounts. Amino acid derivatives may besimple esters or amides or complex peptides.

Suitable emollients include those agents known for softening the skinwhich may be selected from hydrocarbons, fatty acids, fatty alcohols andesters. Petrolatum is a common hydrocarbon type of emollientconditioning agent. Other hydrocarbons that may be employed includealkyl benzoate, mineral oil, polyolefins such as polydecene, andparaffins, such as isohexadecane. Fatty acids and alcohols typicallyhave from about 10 to 30 carbon atoms. Illustrative are myristic,isostearic, hydroxystearic, oleic, linoleic, ricinoleic, behenic anderuicic acids and alcohols. Oily ester emollients may be those selectedfrom one or more of the following, triglyceride esters, acetoglycerideesters, ethoxylated glycerides, alkyl esters of fatty acids, etheresters, polyhydric alcohol esters and wax esters. Additional emollientsor hydrophobic agents include C₁₂ to C₁₅ alkyl benzoate, dioctyladipate,octyl stearate, octyldodecanol, hexyl laurate, octyldodecylneopentanoate, cyclomethicone, dicapryl ether, dimethicone, phenyltrimethicone, isopropyl myristate, caprylic/capric triglycerides,propylene glycol dicaprylate/dicaprate and decyl oleate.

Suitable humectants include various polyhydric alcohols, especiallypolyalkylene glycols and, more preferably, alkylene polyols and theirderivatives. Exemplary humectants include propylene glycol, dipropyleneglycol, polypropylene glycol, polyethylene glycol, sorbitol,2-pyrrolidone-5-carboxylate, hydroxypropyl sorbitol, hexylene glycol,xylitol, ethoxydiglycol 1,3-butylene glycol, 1,2,6-hexanetriol,glycerin, ethoxylated glycerin, propoxylated glycerin, compatiblesolutes, such as ectoin, hydroxectoin, taurines, carnithine, acetylcarnithine and mixtures thereof. When employed in effective amounts,generally from 1 to 30%, preferably from 2 to 20%, by weight of thetopical composition, these additives serve as skin moisturizers as wellas reduce scaling and stimulate the removal of built-up scale from theskin.

Suitable anti-inflammatory ingredients include, but are not limited to,bisabolol, curcurmin and its derivatives, retinoids, flavonoids,meroterpenes (such as Bakuchiol or its derivatives) and otherpolyphenolics etc. These and other anti-inflammatory agents, as well asadditional anti-oxidants and the like, are disclosed in Gupta et. al.(US 2005/0048008A1) which is incorporated herein by reference in itsentirety.

Examples of self-tanning ingredients include, but are not limited to,dihydroxyacetone and erythrulose.

It is to be appreciated that many of the specific ingredients mentionedabove, while presented in just one or two classifications, actuallymanifest a plurality of properties and could rightfully be listed in twoor more of the above classes. This is particularly so for themeroterpenes, especially bakuchiol, which has been shown to possess manydifferent beneficial characteristics when applied to skin and are alsoshown to have gene modulation properties as well. (See Jia et. al.—US2006/0251749A1 and Chaudhuri—US2008/0286217A1, US2009/0137534A1 and US2009/0036545A1; all of which are hereby incorporated herein by referencein their entirety).

The present inventive composition may also include one or more skinpenetrants. These are additives that, when applied to the skin, have adirect effect on the permeability of the skin barrier: increasing thespeed with which and/or the amount by which certain other compounds,especially the active compounds, like the alkanoyl isohexides, are ableto penetrate into the skin layers. Exemplary organic penetrationenhancers include dimethyl sulfoxide; dimethyl isosorbide, dimethylisomannide, diethyl isoidide, diethyl isosorbide, diethyl isomannide,isopropyl isosorbide, isopropyl isomannide, isopropyl isoidide,isopropyl myristate; decyl, undecyl or dodecyl alcohol; propyleneglycol; polyethylene glycol; C₉₋₁₁, C₁₂₋₁₃ or C₁₂₋₁₅ fatty alcohols;azone; alkyl pyrrolidones; lecithin; etc. Surfactants can also be usedas penetration enhancers. Additionally, since the alkanoyl isohexidesalso affect cross-epidermal transport, they too may be used as skinpenetration enhancers for other skin care or treatment products.

Other optional adjunct ingredients for the compositions of the presentinvention include preservatives, waterproofing agents, fragrances,anti-foam agents, plant extracts (Aloe vera, witch hazel, cucumber,etc), opacifiers, stabilizers, skin conditioning agents colorants, andthe like, each in amounts effective to accomplish their respectivefunctions.

The amount of the inventive composition that is to be applied to theskin is the amount that provides the desired effect of improvement inskin health and or appearance. To some extent, the amount depends uponthe form of the inventive composition and its mode of application. Forexample, a spray formulation may be applied so as to provide a light,even coat on the skin. Lotions, creams, gels and the like are typicallyapplied at a rate of about 0.1 to about 10 mg/cm², preferably from about1 to about 3 mg/cm², to the skin. This rate generally provides a thineven coating on the skin surface.

The skin conditioning compositions according to the present inventionmay be applied to the skin for so long a necessary to address aparticular problem or issue or they may be applied on a continuous basisas a matter of general skin cleansing and maintenance. Where thecompositions are to be employed to address particular problems orissues, it is best to employ compositions wherein the strength orconcentration of the active alkanoyl isohexide is relatively high.However, for compositions that are to be used on a continuous basis,e.g., weekly, daily, or even more frequently, a lower strength orconcentration product may be suitable. In general, the desire is toattain the desired effect while minimizing the use and exposure ofchemical agents.

In addition to those benefits of the inventive compositions mentionedabove, it is to be appreciated that the continual, preferably daily, useof the compositions of the present invention, regardless of whether oneis manifesting a problem to be addressed or not, provides a number ofadditional benefits to one's skin. For example, the long-term use of theinventive compositions may help with thickening the keratinous tissue(i.e., building the epidermis and/or dermis layers of the skin), therebypreventing and/or retarding atrophy of human skin; preventing and/orretarding the appearance of spider veins and/or red blotchiness on humanskin; preventing and/or retarding the appearance of dark circles underthe eye; preventing and/or retarding sallowness and/or sagging of humanskin; soften and/or smooth lips; preventing and/or relieving itch ofhuman skin, regulating skin texture (e.g. wrinkles and fine lines),improving skin color (e.g. redness, freckles); preventing and/orretarding the ingress and adverse effect of environmental irritants,sensitizers, and allergens through the skin barrier, and the like. Inessence, the long-term benefits of the continual use of the compositionsof the present invention include the lessening or delayed manifestation,possibly even the prevention or repair, of skin damage owing to thenatural process of skin aging as well as skin damage due toenvironmental factors, especially sun exposure. Generally, the use ofthese compositions will manifest itself in an overall improved skinquality as compared to skin which has not been treated with acomposition according to the present invention, and, most especially, towhich no effective product had been applied on an on-going basis

EXAMPLES

Having described the invention in general terms, Applicants now turnattention to the following examples in which specific formulations andapplications thereof are evaluated. In the following examples, unlessotherwise indicated, all temperatures are set forth in degrees Celsiusand all parts and percentages are by weight.

In the following discussion and examples the “modulating” or“regulating” of a gene refers to the ability of a compound to affect theability of that gene to induce the production of the correspondingprotein, lipid or enzyme, which protein, lipid or enzyme is then capableof performing at least one of its biological activities to at least someextent. In assessing performance, most often only those tests or samplesin which at least a ±130% change in gene expression was manifested wereconsidered, expressed as a ±1.3 fold. Up-regulation (presented as apositive fold change) is a process which occurs within a cell triggeredby a signal (originating internal or external to the cell) which resultsin an increased expression of one or more genes and, as a result, anincrease in, e.g., the protein(s) encoded by those genes. Converselydown-regulation (presented as a negative fold change) is a processresulting in decreased gene and corresponding protein expression.Up-regulation occurs for example when a cell is deficient in some kindof receptor. In this case, more receptor protein is synthesized andtransported to the membrane of the cell and thus the sensitivity of thecell is brought back to normal, reestablishing homeostasis.Down-regulation occurs for example when a cell is overly stimulated by aneurotransmitter, hormone, or drug for a prolonged period of time andthe expression of the receptor protein is decreased in order to protectthe cell. This homeostasis can be achieved by using external agent withbeneficial effects to skin.

Additionally, as used herein, the term, “p-value” is used to mean theprobability that the results were not significant: for example, ap-value of 0.05 means that there are 5 chances in 100 that the resultsare not significant. The term “fold change” refers to the extent, ascompared to the control, typically DMSO control, that the activeproduced an increase or decrease in gene expression as evidenced by anincrease or decrease in the appropriate or related gene product. A 1.5fold increase means that 1.5 times as much of the corresponding geneproduct was produced in those cells exposed to the active as compared tothose only exposed to the DMSO control.

In performing the gene assays reported below, samples of EpiDerm tissuesobtained from Mattek of Ashland, Mass., were cultured according to themanufacturer's instructions. Unless otherwise specified, alltissues/cells were treated with 50 μg/ml of the test compoundsspecified. The tissue samples were incubated in the specified test andcontrol solutions for a period of 48 hours. Following the incubationperiod, the tissue samples were harvested, frozen in liquid nitrogen,and subjected to RNA extraction with a Qiagen kit. The quality of theextracted RNA was validated twice by electrophoresis and/or spectrometry(following extraction and before microarray analysis) in accordance withthe methodology of Hangbao Ma et. al., Application of Real-TimePolymerase Chain Reaction (RT_PCR), The Journal of American Science,2(3), 2006.

Example 1—Isohexide Esters

An isohexide composition was prepared from purified sunflower oilcontaining 70% linoleic acid and approximately 30% oleic acid. Theisohexide was formed by refluxing Isosorbide with 2.2 moles of mixedfatty acids [obtained from sunflower oil with a typical fatty acidcomposition: C₁₆ (palmitic acid)=4%, C₁₈ (stearic acid)=1%,C_(18:1)(oleic acid)=29%, C_(18:2) (linoleic acid)=64% C_(18:3)(linolenic acid)=0.4%] in cyclohexane using p-toluene sulfonic acid as acatalyst with continuous removal of water. After completion of thereaction, the organic layer was washed with 10% sodium bicarbonatesolution, followed by water till pH is neutral. The solvent wascompletely removed by distillation, then, the residue was distilledusing high vacuum. The yield of the isohexide diesters (Isosorbidedi-(sunflowerseedate) was about 75% based on isosorbide used. Theisohexide diesters composition was obtained with a diester/monoestercontent (GC) of 99.6% with a relative density of 0.97 g/ml. Theresulting isohexide ester composition was found to further comprise offree fatty acids (0.1%), isosorbide (<0.1%) having acid value 0.21 (mgKOH/g), moisture (0.13%), sulfated ash (0.04%).

Example 2—Cell Differentiation

To show the benefit of the use the alkanoyl isohexide of the presentdisclosure against other prominent actives for influencing filaggrinwhich plays a key role in keratinization and cell differentiation andoverall skin health, including proper formation of the skin barrier, theperformance of the isosorbide dilinoleate composition formed accordingto Example 1 was compared with that of ethyl linoleate (sunflower seedoil used in Example 1) and isosorbide dicaprylate (IDC) (Hydrasynol™DOI—Sytheon Ltd., U.S. Pat. No. 8,496,917, whose contents areincorporated herein by reference). The results are shown in Table 2.

TABLE 2 Fold change v control Gene Full Name Key Biological FunctionsIDL EL IDC SASPase Skin-specific Regulates stratum corneum hydration 3.8−1.3 (NS) 0 retroviral- through profilaggrin to filaggrin processing;like aspartic Involved in prevention of fine wrinkles (J protease BiolChem, 281(37): 27512-27525, 2006) FLG Filaggrin Involved in epidermaldifferentiation & skin 2.0 −1.3 0 barrier formation; Mutations in thefilaggrin gene causes ichthyosis vulgaris; Filaggrin degrades to aminoacids - NMF FLG2 Filaggrin 2 Involved in epidermal differentiation &skin 1.9 −1.5 0 barrier formation; Mutations in the filaggrin genecauses ichthyosis vulgaris; Filaggrin degrades to amino acids - NMF IVLInvolucrin Protein precursor of the epidermal cornified 1.4 −1.5 (NS)1.5 envelope; Contributes to the formation of a cell envelope thatprotects corneocytes in the skin (Exp Dermatol, 9(6): 431-438, 2000)KPRP Keratinocyte Involved in keratinocyte differentiation (J 1.8  1.2(NS) 0 Proline-rich Invest Dermatol, 124: 995-1000, 2005; JBC, Protein278, 22781-22786, 2003) CRNN Cornulin A marker of late epidermaldifferentiation; 1.6 −1.2 0 Down-regulated in eczema (Allergy, 64(2):304-311, 2009) DHRS9 Dehydrogenase Converts retinol to retinoic acid(RA) which 2.9  2.4 0 9 enhances keratinocyte differentiation (BiochimBiophys Acta, 1821: 152-167, 2012) CDSN Corneodesmosin Key to epidermalbarrier integrity, Absence 1.7  1.3 causes strong inclination to atopicsymptoms, essential epidermis adhesion molecule (Eur J Dermatol, 21:35-42, 2011

As evident from Table 2, IDL provided a significant increase inFilaggrin (FLG), Filaggrin 2 (FLG2), skin aspartic protease (SASPase),KPRP Keratinocyte proline-rich protein), CRNN (Cornulin) levels in humanfull thickness epidermal tissue whereas no such up-regulation of thesegenes were noticed for EL or IDC.

Example 3—Genes Involved in Lipid Synthesis

As noted in the background section, lipids also play a key role in theformation and function of the skin barrier, especially with respect totransport through the lipid bilayer as well as repair following injury.Similar to Example 2, a comparative series of gene assays were performedto show the relative performance of the compounds of the presentinvention with other known and effective skin treatment actives. Asbefore, isosorbide dilinoleate formed in accordance with Example 1 wascompared with ethyl linoleate (sunflower seed oil used in Example 1) andisosorbide dicaprylate (IDC). The genes evaluated and their expressionprofiles are shown in Table 3.

TABLE 3 Fold change v control Gene Full Name Key Biological FunctionsIDL EL IDC SMPD3 Sphingomyelin Catalyzes hydrolysis of 2.1 1.7 0phosphodiesterase 3 sphingomyelin to ceramide GBA Glucosyl ceramidase/Converts Glucosyl ceramide to 1.4 0 1.3 (NS) Glucocerebrosidase ceramide(J Lipd Res, 49(4): 697- 714, 2008) ABCA12 ATP-binding cassetteTransports Glucsosyl ceramide to 1.4 0 0 transporter A12 lamellar bodies(J Lipid Res, 49(4): 697-714, 2008) ABCG1 ATP-binding casseteIntracellular sterol transporter; 1.8 0 0 transporter G1 & G4 Facilitateredistribution of specific intracellular sterols away from theendoplasmic reticulum (Proc Natl Acad Sci, USA, 108(49): 19719- 19724,2011) DHCR24 24-dehydrocholesterol Involved in the conversion of 1.4 0 0reductase desmosterol to cholesterol. Plays crucial role for skindevelopment and its proper function (J Invest Dermatol, 126(3): 638-47,2006) ABHD5 CGI-58 acid lipase Generates diacylglycerides and 1.8 0 0FFAs from triacylglycerides (J Lipid Res, 49(4): 697-714, 2008) ELOV2Elongation of very Found not only as constituents of 1.4 0 0 long chainfatty acids cellular lipids such as sphingolipids andglycerophospholipids but also as precursors of lipid mediators (BiomolTher (Seoul), 22(2): 83- 92, 2014)

Barrier repair after injury involves trafficking of lamellar bodies (LB)to the SC, where they secrete their contents, and activation of severalgenes, including the ATP-binding cassette sub-family A, member 12(ABCA12), an essential lipid transporter in the epidermis (and whosemal-expression is responsible for harlequin ichthyosis and lamellarichthyosis type 2), and lipid metabolism enzymes, glucocerebrosidase(GBA) and acid sphingomyelinase (SMPD1). Cholesterol, free fatty acid,and ceramide synthesis all are also increase following skin barrierdisruption and are essential for barrier repair (Borkowski et al, JInvest Dermatol, 133(8):2031-2040, 2013). Surprisingly, as shown inTable 3, of the three materials evaluated, with the exception of SMPD3which was also up-regulated with EL, none of the genes screened andrelated to lipid metabolism were up-regulated with EL or IDC.

Example 4—Barrier Building

Barrier function and development are keys to proper skin function andhealth. A comparative series of gene assays were performed on barrierfunction related genes to show the relative performance of theisosorbide dilinoleate of Example 1 with ethyl linoleate (sunflower seedoil used in Example 1). The genes/enzymes assayed and the geneexpression profiles are shown in Table 4.

TABLE 4 Fold change v control Gene Full Name IDL EL DSG1 Desmoglein 11.3 −1.7 DSG2 Desmoglein 2 2.0 0 PKP1 Pakophilin 1 1.3 0 PKP2 Pakophilin2 1.3 −1.3 EVPM Envoplakin 1.5 0 CLD4 Claudin 4 1.5 1.3 CLD17 Claudin 172.8 1.3 GJB4 Gap Junction Beta 4 1.4 0

These genes play important roles in relation to desmosomes, whichprovide strong intercellular cohesion for maintaining the integrity ofcells & tissues exposed to continuous mechanical stress (Cells Mol LifeSci, 72(24):4885-4897, 2015) and tight junctions (TJ) and gap junctions(GJ) which contribute to the epithelial barrier function by preventingleakage of solutes through the intercellular space (J Deramatol Sci,70(1):12-18, 2013). As indicated, IDL provided a marked improvement orup-regulation in these genes as compared to EL.

Example 5—Keratin Building

Keratins, like many other proteins, play an important role in barrierformation and epidermal differentiation. During differentiation, allstratified epithelia are keratinized and some of these keratinizedstratified epithelia are subsequently cornified and form the stratumcorneum. While long recognized for their importance, recently, newfunctions of keratins and keratin filaments in cell signaling andintracellular vesicle transport have been discovered (J Anatomy, 214(4):516-559, 2009). Among the key keratin genes is K1. K1 is involved inepidermal differentiation in the basal layer and required to interactwith FLG during differentiation. In this example, the performance of theisosorbide dilinoleate of Example 1 was compared to that of ethyllinoleate (sunflower seed oil used in Example 1) in regulating orimpacting a number of keratin genes. The genes evaluated and theexpression profiles attained are presented in Table 5.

TABLE 5 Fold Change vs Control Gene IDL EL K1 1.7 −1.3 K23 1.5 −1.2 K311.5 0 K78 1.6 0 K80 1.4 −1.1

As seen in Table 5, IDL had a marked improvement and upregulation inkeratin genes whereas EL had no effect or a negative effect.

Example 6—Late Cornified Envelope

LCE is a family of late cornified envelope proteins that are expressedin skin (J Invest Dermatol, 124(5):1062-1070, 2005) and are precursorsof the cornified envelope of the stratum corneum, the outermost layer ofthe epidermis. LCE is part of the epidermal differentiation complex,which comprises many genes encoding structural and regulatory proteinsthat are of crucial importance for keratinocyte differentiation andstratum corneum properties. To assess the effect of the alkanoylisohexide on LCEs a gene assay was performed comparing the performanceof the isosorbide dilinoleate of Example 1 with ethyl linoleate(sunflower seed oil used in Example 1) in regulating or impacting anumber of LCE genes. The genes evaluated and the expression profilesattained therewith are shown in Table 6.

As seen in Table 6, while both test samples provided a positive impacton LCE genes, i.e., an up-regulation on LCE protein production, the IDLhad a marked higher performance on most all of the genes assayed.

TABLE 6 Fold change v control Gene IDL EL LCE1A 2.4 1.5 LCE1B 2.1 1.4LCE1C 2.8 1.4 LCE1D 2.8 1.6 LCE1E 2.5 1.5 LCE1F 2.7 1.9 LCE2 1.8 1.6LCE2B 2.1 1.8 LCE2C 1.7 1.7 LCE2D 1.6 1.6 LCE3C 1.7 1.7 LCE3E 1.6 1.4LCE6A 1.5 1.3

Example 7—Involucrin and Filaggrin Proteins

Skin samples of a 55 year old female were cleaned and cut into 3×3 mmsize. The pieces were placed (epidermis upwards in air contact) into a24 well-plate (3/well) in a volume of 0.3 ml of culture medium which waschanged every 2-3 days. Concurrent with the change of culture medium,the epidermis of each of the skin explants were treated with (1) controlcream (no IDL), cream (2% IDL) and 4% cream (4% IDL) using sterilespatula. The cream formulation applied is the same as used in theclinical trial set forth in Example 154 below with the exception thatthe level of IDL is as presented here. After 14 days, the skin explantswere dried to eliminate culture medium and placed in a freezer at −70°C. for subsequent testing.

The skin samples were then quantified for filaggrin and involucrin. Herethe skin samples were subjected to sonication in PBS at 2-4° C., afterwhich each skin lysate was made up to 1 ml and a sample of 10 μl eachtaken for protein assay. Further, a concentration of 2 μg/ml wasprepared for each treatment following which a microplate was then coatedwith 100 μl of the skin lysates and incubated over night at 4° C. Afterwashing, the antibodies involucrin (Santa Cruz, catalog n^(o) sc-21748)and filaggrin (sigma, catalog n^(o) hpa030188) were added (100 μl/well)and the treated samples incubated 2 hours at room temperature. Themicroplate was then washed and a second antibody conjugated toperoxidase was added. After 1 hour of incubation at room temperature,the microplate was washed and the peroxidase-substrate was added in thedark for 20 minutes at room temperature. The optical densities wererecorded using a microplate reader at 450 nm. It was found that IDL at aconcentration of 2% provided a 13% and 51% increase in involucrin andfilaggrin, respectively. At 4%, the effect was even markedly higher, 52%and 88% increases, respectively. This is especially significant since a10-20% increase in filaggrin is predicted to be therapeutic for orpreventative of eczema (J Invest Dermatol, 132:751-762, 2012).

Example 8—Antioxidant Shield

Small Proline-Rich Proteins (SPRPs) provide a natural antioxidant shieldto the skin due to the presence of high level of proline. These proteinsact as first line of defense against reactive oxygen species (ROS). Alsoduring wound healing, SPRR proteins directly reduce toxic ROS levels.This activity is directly related to their ability to promote cellmigration and is essential in order to allow wound closure (Cabral etal., J Biol Chem, 276:19231-19237, 2001; J Invest Dermatol,13_1435-1441, 2011). They also serve as a flexible linker of structuralproteins in the Cornified envelope (CE) and confer elasticity.Similarly, glutathione S-transferase (GST) is the key enzyme involved ineliminating carcinogens and harmful macromolecules from cells. GPXreduces lipid hydroperoxides alcohols and hydrogen peroxide water.

In an effort to assess the impact of the alkanoyl isohexides of thepresent disclosure in addressing ROS and defending against oxidationproducts, the impact of IDL was compared to EL, as above, on a number ofSPRP and GST genes. The genes evaluated as well as the expressionprofiles thereof are presented in Table 7.

The key antioxidant providing or shielding genes are the SPRPs and, asevident from Table 7, the IDL provided a marked enhancement in orup-regulation of the SPRP genes, attesting to powerful antioxidanteffectiveness in protection skin against and repairing skin from harmfuleffects of the environment, especially sunlight, and other ROS and likedamaging species. Additionally, the IDL had a marked or up-regulation ofthe glutathione genes, indicative of excellent damage control andprotective effects against harmful macromolecules and the like whereasEL showed no effect.

TABLE 7 Fold Change vs Control Gene Full Name IDL EL SPRR4 SmallProline-Rich Protein 4 2 1.5 SPRR3 Small Proline-Rich Protein 3 3.1 1.5SPRR2G Small Proline-Rich Protein 2G 1.3 1.2 SPRR1B Small Proline-RichProtein 1B 1.4 0 GSTT2 Glutathione S-transferase 1.7 0 theta 2 GSTT2BGlutathione S-transferase 1.4 0 theta 2B-1 GPX3 Glutahione Peroxidase 31.5 0

Example 9—Transcription Factor Regulatory Activity

While the alkanoyl isohexides are shown to have a marked beneficial,up-regulating effect on a number of genes associated with skin healthand building, it is also to be noted that is has a beneficial impact ona number of genes that are adverse to skin health as well. Here, theisohexides induces a down-regulation in a number of genes associatedwith skin damage and disease.

In this experiment TNFα induced transcription regulatory activity ofNFκB in murine myoblasts C2C12 cells transfected with an NFκB luciferasereporter gene were evaluated by adding the luciferase assay reagent toeach well and recording luminance reading. The method followed isgenerally as presented in J Yang et al, Food Chem, 160:338-345, 2014.The results are shown in Table 8 which presents the % reduction intranscription regulatory activity of NFkB.

TABLE 8 % Reduction in transcription regulatory Amount activity of NFκBused IDL EL 100 ug/ml  −23 −13 50 ug/ml −8 −8 25 ug/ml −3 −7

As seen in Table 8, IDL is almost two times as effective in reducingtranscription regulatory activity of NFkB at 100 μg/ml.

Example 10—Anti-Inflammatory Activity

Chemokines are essential mediators in the pathophysiology ofinflammatory diseases. The chemokine family is divided into four classesbased on the number and spacing of their conserved cysteines. In atopicdermatitis (skin biopsy, micoarray) and in psoriasis, several CCLchemokines have been shown to be up-regulated (J Allergy & ClinImmunology, 12(6):1195-1202, 2003). Under UVB exposure, severalchemokines are up-regulated, with CXCL5 shown to be the cause ofUVB-induced inflammatory pain (J M Dawes et al., Sci Transl Med. 3(90),90-ra60, 2011). S100A7A (calcium binding protein) exhibitspro-inflammatory activity and is up-regulated in atopic dermatitis andpsoriatic skin (J Immunol, 181(2):1499-1506, 2008).

As with the prior examples, gene assays were conducted comparing theimpact of the isosorbide dilinoleate of Example 1 with ethyl linoleateon a number of chemokines and inflammatory response. The identity of thegenes assayed and the gene expression profiles attained thereby areshown in Table 9.

As seen in Table 9, IDL significantly down-regulated 9 pro-inflammatorymediators whereas EL only down-regulated 2. Additionally, though notshown above, IDL also provided a 2.1 fold up-regulation of dermokinewhereas EL had no effect. Dermokine had been shown to decrease CXCLchemokines in keratinocyte cultures (J Dermatol Sc., 70(1):34-41, 2013),further evidencing the anti-inflammatory response and activity of IDL.

TABLE 9 Fold Change vs Control Genes Full name IDL EL CCL2 Chemokine(C-C motif) ligand 2 −1.4 0 CCL5 Chemokine (C-C motif) ligand 5 −1.3 0CCL8 Chemokine (C-C motif) ligand 8 −1.3 0 CCL20 Chemokine (C-C motif)ligand 20 −1.5 0 CXCL2 Chemokine (C-X-C motif) ligand 2 −1.8 −1.3 CXCL5Chemokine (C-X-C motif) ligand 5 −1.4 −1.3 TNF Tumor necrosis factor−1.8 0 IL20 Interleukin 20 −1.7 0 S100A7A S100 calcium-binding proteinA7A −1.5 0 DMKN Dermokine +2.1 0

Example 11—Pro-Inflammatory Arachidonates

A second series of pro-inflammatory genes were compared, again with thesame IDL and EL test materials. The genes assayed and the geneexpression profiles attained therewith are presented in Table 10.

As seen in Table 10, IDL down-regulated all four pro-inflammatorymediators whereas EL only down-regulated three.

TABLE 10 Fold change vs control Gene Full Name IDL EL COX2Cyclooxygenase 2 −1.4 −1.3 PLCH2 Phospholipase C, eta 2 −1.4 −1.3 PLCG2Phospholipase C, gamma 2 −1.3 −1.3 PLA2G4F Phospholipase A2, gr IVF −1.30

Example 12—Recovery of Cytokine-Induced Skin Tissue Damage

Samples of epidermal tissue (Mattek) were treated with Cytokine (IL-17,IL-21, TNF-α) for 24 hrs: a control was also set aside and treated withsolvent only. Following cytokine treatment, one sample was set aside andthe remaining were treated with either 10 μl of IDL (50 μg/ml) orTazarotene (500 μg/ml) for 5 days and reapplied twice. Following fulltreatment, the tissues samples were rinsed and incubated with MTT fordetermining tissue viability and quantified with Molecular Devicesmicroplate reader MAX190 at 550 nm. The samples were stained withHematoxylin & Eosin (H&E) to visualize epidermal damage and a separateset of samples were treated with anti-filaggrin antibody to quantifyfilaggrin. Images were captured with color Discovery 15 CMOS microscopevideo camera using ISCapture software.

Photomicrographs of the H&E stained samples are presented in FIG. 1wherein (a) is the solvent control, (b) is the cytokine treated sample,(c) is the cytokine treated sample with IDL and (d) is the cytokinetreated sample with Tazarotene. As evident from the photomicrographs,cytokine treatment resulted in significant damage to the epidermis ascompared to the control. The treatments with both the IDL and tazarotenetended to protect or repair the damage to the stratum corneum. Similarresults were attained in the photomicrographs of filaggrin assessmentswhere both test materials appeared to exhibit a more homogeneousfilaggrin labelling in the upper sections of the epidermis and a betterpreserved stratum corneum as compared to the cytokine treated samples.

Example 13—Desquamation

The normal physiology of the skin requires both the proper formation andthe controlled shedding (desquamation) of the cornified layers.Kallikreins play a key role in the modulation of desquamation. Theimpact of IDS and EL on a number of kallikreins was evaluated to assessthe likely impact, if any, of IDL and El on desquamation. Thekallikreins evaluated were kallikrein 5 (KLK5), kallikrein 6 (KLK6),kallikrein 7 (KLK7), kallikrein 10 (KLK10) and kallikrein 12 (KLK12).Additionally, the impact of IDL and EL on serine peptidase inhibitor,Kazal type 5 (SPINK5), a key regulator of protease activity whosedysfunction leads to atopic conditions, was also evaluated. Thecomparative gene expression profiles are presented in Table 11.

The results shown in Table 11 clearly demonstrate that IDL has a markedup-regulation effect on genes and enzymes associated with the regulationand modulation of desquamation.

TABLE 11 Fold change v control Gene Full Name Key Biological FunctionIDL EL KLK5 kallikrein 5 Involved in desquamation 2.1 1.3 KLK6kallikrein 6 and filaggrin degradation 1.9 1.3 to NMF KLK7 kallikrein 7Involved in desquamation 1.6 0.2 KLK10 kallikrein 10 but not filaggrindegrada- 1.6 0.2 KLK12 kallikrein 12 tion 2.7 0.1 SPINK5 Serinepeptidase Plays critical role in epi- 1.8 0.2 inhibitor, Kazal dermalbarrier function by type 5 regulating protease activity, Dysfunctionleads to atopic conditions

Example 14—Human Clinical Study

Eighteen healthy but photo-aged female subjects, aged 46-60 years, wererecruited to conduct a blind study. All subjects had abstained from theuse of moisturizing products and used only simple soap, for at least oneweek prior to treatment. All test products were supplied in identicalcontainers. Subjects were instructed on the use of the cream—twice dailymorning and evening applications to the entire face for 12 weeks.Clinical assessments of the skin of the face were performed for allparticipants at baseline and following 4, 8 and 12 weeks of product use.The following parameters were assessed at each visit by an expert graderand the panelists' self-evaluation: Fine Lines/Wrinkles, Roughness,Dryness, Skin Tone, Skin Elasticity and Firmness, Radiance, Erythema,Brightening and Overall Eye Area Appearance. Assessment for eachparameter was performed at baseline using the following five pointordinal severity scale: 0=None; 1=Minimal; 2=Mild; 3=Moderate; 4=Severe.Data points were then assessed as the % variation from the baseline.

Silicone Analysis Profilometry: At each visit, a single silicone replicawas made of the target area and a photographic record was kept of thistarget for subsequent relocation. Comparative analysis of skinprofilometry was conducted, using surface roughness and wrinkle depthanalysis. The heights of the replicated wrinkles were measured usingMiyomoto Surftest profilometer. Ry (depth) and Ra (mean roughness) wererecorded at each time of measuring operation. The area scanned from eachsample was clearly mapped so as to determine the same area in respectiveWeek 4, Week 8, and Week 12 samples.

Photo Booth: At each time point, a series of high resolution digitalphotographs was collected using a photo booth equipped with Canon G7Digital Camera 10 MP, 6×zoom. Subject positioning was reproduced uponreturn visit. A light booth was used so as to provide controlledreproducible light conditions. The booth consists of an array of 8equally spaced fluorescent tubes in a semicircular configuration. Thesoftware driven system allows the position and expression of the testsubjects to be aligned to a high degree.

Method of Assessment & Product Application. The baseline for eachsubject was determined by the expert grader who performed assessment ofthe panelist's face and eye area for all the parameters as describedbefore. Photographs were conducted using a photo booth with a 3-pointhead restraint with photographs taken with frontal view, 45 degrees tothe right, and 45 degrees to the left at each time point (Day 0, Week 4,Week 8, and Week 12). A replica ring was used to delineate the wrinklesite in the crow's feet area. Silflo was applied on the site, allowed todry for approximately five minutes and the replica was removed gentlyfrom the site.

Product Application: Test Materials, which comprised a cream formulationas set forth in Table 12, were distributed to the subjects. Subjectswere asked to gently massage a small amount of the test material to thecrow's feet and eye area and then smooth over the whole face. They wereasked to apply twice a day for twelve weeks. A study diary was given tothe panelists in order to list the time of application, the dates andany subjective comments that they might have in regards to the testproduct. The Test Material was prepared by combining the ingredients ofPhase A-1 and then dispersing Phase A-2 in Phase A-1 while stirring andheating 75° C. The Phase B ingredients were similarly combined and thenheated to 75° C. Phase B was then added to the combined Phase A-1/A-2with good mixing. The mixture was then homogenized at high speed for 5minutes. The homogenized mixture was allowed to cool to 45° C. afterwhich phase C was slowly added while gently stirring until the combinedmixture is homogeneous. The formulation was determined to have a pHvalue of 5.5 and a viscosity of 30,000-45,000 cps (Brookefield RVT,spindle C, Helipath) at 25° C.

Week 4, 8 and 12 weeks: Panelists returned to the study site after week4, week 8, and week 12, of product use. At each study visit, panelistswere clinically evaluated in the same manner as at the baseline visit.

Results. The initial results of the clinical study are presented inTables 13 (Expert Evaluation) and 14 (Panelists' Self-Evaluation). Asseen in Tables 13 and 14, IDL manifests statistically significanteffects on multiple parameters of aging signs and also improvement inbarrier function. Similar improvements in skin appearance were seenbetween 8 and 12 weeks data vs, the base line using photography andsilicone replica.

TABLE 12 Hydrating Skin Lotion % INCI name Trade Name/Supplier w/w PhaseA-1 Water (demineralized) QS Disodium EDTA 0.1 Glycerin Glycerin99%/Ruger 3.0 Phase A-2 Sodium acrylates copolymer, Lecigel/Lucas Meyer0.8 Lecithin Phase B Caprylic/Capric Triglycerides Myritol 318/BASF 5.0Steareth-20 Brij S20/Croda 1.5 Cholesterol Cholesterol NF/Spectrum 0.3Stearyl/PPG-3 Myristyl Ether Liquiwax PolyIPL/Croda 0.5 DimerDilinoleate Butyrospermum Parkii (Shea) Shea Butter Refined/Rita 1.0Butter Glyceryl Stearate Cerasynt Q/Ashland 2.5 Cetyl Alcohol CrodacolC-70/Croda 1.0 Dimethicone DC, 200/50 CST/Dow 2.0 Corning IsosorbideDisunflowerseedate HydraSynol ™ IDL/ 2.0 or 3.0 (present invention)Sytheon or 4.0 Phase C Phenoxyethanol, Ethylhexyl- Euxyl PE 9010/Schulke0.85 glycerine Lavander Oil Lavander Oil/Premier 0.10

TABLE 13 Expert Comments % Improvements* vs baseline (after using alotion containing 3% Isosorbide disunflowerseedate (IDL) for) Parameters4 weeks 8 weeks 12 weeks Roughness −50 −75 −80 Dryness −46 −79 −85 Finelines & −15 −21 −32 Wrinkles Skin Tone −15 −31 −39 Elasticity & −20 −34−49 Firmness Erythema −10 (p = 0.01) −22 −33 Brightening  −13 (p =0.002) −20 −33 Overall eye −23 −34 −48 area appear- ance *Statisticalsignificance: 4, 8 and 12 weeks results vs initial - p ≤ 0.000 exceptparameters erythema and brightening; NS = Not statistically significant

TABLE 14 Panelists' Comments % Improvements* vs. baseline (after using alotion containing 3% Isosorbide disunflowerseedate (IDL) for) Parameters4 weeks 8 weeks 12 weeks Roughness −23 −40 −60 Dryness −33 −42 −61 Finelines & −9 (p = 0.01) −19 (p = 0.002) −26 Wrinkles Skin Tone −10 (p =0.01) −13 (p = 0.005) −33 Elasticity & −19 −26 −48 Firmness Erythema −6NS −9 NS −29 (p = 0.01) Brightening −12 (p = 0.005) −16 (p = 0.003) −37Overall eye −25 −29 −39 area appear- ance *Statistical significance: 4,8 and 12 weeks results vs initial - p ≤ 0.000 except parameters finelines & wrinkles, skin tone, brightening and erythema (see Table)

Furthermore, combining with other actives, such as, anti-aging, skinlightening/even-toning, sunscreens, anti-acne, self-tanning ingredient,additional improvements in skin appearance can be achieved.

Example 15—Exemplary Product Formulations

A series of consumer-type skin care product formulations were preparedto exemplify various end-use applications for the isohexide compoundsand compositions of the instant application.

Formulation 15-A embodies a Super Hydrating Skin Lotion with Aquaporin 3booster and its formula is presented in Table 15. Formulation 15-A wasprepared by combining the ingredients of Phase A-1 and then dispersingPhase A-2 in A-1 while stirring and heating to 75° C. The Phase Bingredients were then combined and heated to 75° C. and subsequentlyadded to the combined Phase A-1/A-2 with good mixing. The mixture wasthen homogenized at high speed for 5 minutes after which the mixture wasallowed to cool to 45° C. Thereafter Phase C was slowly added whilestirring and the same continued to be stirred until mixture ishomogeneous. The resultant composition was found to have a pH value of5.5 and a viscosity of 30,000-45,000 cps (Brookefield RVT, spindle C,Helipath) at 25° C.

TABLE 15 Super Hydrating Skin Lotion with Aquaporin 3 booster % INCIname Trade Name/Supplier w/w Phase A-1 Water (demineralized) QS DisodiumEDTA 0.1 Glycerin Glycerin 99%/Ruger 3.0 Phase A-2 Sodium acrylatescopolymer, Lecigel/Lucas Meyer 0.8 Lecithin Phase B Caprylic/CapricTriglycerides Myritol 318/BASF 5.0 Steareth-20 Brij S20/Croda 1.5Cholesterol Cholesterol NF/Spectrum 0.3 Stearyl/PPG-3 Myristyl EtherLiquiwax PolyIPL/Croda 0.5 Dimer Dilinoleate Butyrospermum Parkii (Shea)Shea Butter Refined/Rita 1.0 Butter Glyceryl Stearate Cerasynt Q/Ashland2.5 Cetyl Alcohol Crodacol C-70/Croda 1.0 Dimethicone DC, 200/50 CST/DowCorning 2.0 Isosorbide Disunflowerseedate HydraSynol ™ IDL/Sytheon 2.0(present invention) Isosobide dicaprylate HydraSynol ™ DOI/Sytheon 2.0(Aquaporin 3 booster) Phase C Phenoxyethanol, Ethylhexyl- Euxyl PE9010/Schulke 0.85 glycerine Lavander Oil Lavander Oil/Premier 0.10

Formulation 15-B embodies an Anti-Aging Hydrating Gel Cream withbakuchiol and IDL: its formulation is presented in Table 16. Formulation15-B was prepared by combining the ingredients of Phase A-1 and heatingto 65° C. Phase A-2 was then dispersed in Phase A-1 with rapid mixing.The Phase B ingredients were then combined and heated to 65° C. andsubsequently added to the combined Phase A-1/A-2 with good mixing. Themixture was then homogenized at high speed for 2 minutes after which themixture was allowed to cool to 45° C. Thereafter Phases D and E wereslowly added while gently stirring until a homogeneous mixture wasattained. The resultant composition was found to have a pH value of 6.0and a viscosity of 35,000-50,000 cps (Brookefield RVT, spindle C,Helipath) at 25° C.

TABLE 16 Anti-Aging Hydrating Gel Cream % INCI name Trade Name/Supplierw/w Phase A-1 Water (demineralized) QS Disodium EDTA 0.10 HydrogenatedLecithin Emulmetik 320/Lucas Meyer 0.75 Glycerin Glycerine 99%/Ruger2.00 PEG-8 Pluracare E 400/BASF 2.00 Niacinamide Niacinamide PC/DSM 2.00Caffeine Caffeine Anhydrous USP/ 0.50 MMP Internationals Butylene GlycolButylene Glycol/Ruger 3.00 Phase A-2 Ammonium acryloyldimethyl-Aristoflex AVC/Clariant 1.10 taurate/VP copolymer Phase BCyclopentasiloxane DC 345/Dow Corning 5.00 Dimethicone DC 200, 50cst/Dow Corning 1.00 Tocopheryl Acetate Vitamin E Acetate/DSM 0.10Isosorbide Disunflowerseedate HydraSynol ™ IDL/Sytheon 2.00 (presentinvention) Oleth-10 Brij O10/Croda 0.50 Bakuchiol Sytenol ® A/Sytheon0.50 Phase D Citrus Aurantium Bergamia Bergamont Oil/Premier 0.15(Bergamot) Fruit Oil Phase E Phenoxyethanol, Ethylhexy- Euxyl PE9010/Schulke 1.00 glycerine

Formulation 15-C embodies a Hydrating Sunscreen Oil having an in-vivoSPF of 25-30. Its formulation is presented in Table 17. Formulation 15-Cwas prepared by combining the ingredients of Phase A and mixing well.The Phase B ingredients were combined and Phase B was then added toPhase A while mixing and heating to 75° C. The mixture was continuallystirred at 75° C. until a clear solution was obtained.

TABLE 17 Hydrating Sunscreen Oil % INCI name Trade Name/Supplier w/wPhase A C-12-15 Alkyl Benzoate Finsolv TN/Innospec 25.0 Propylene GlycolDicaprylate/ Dermol M-20/Alzo 25.0 Dicaprate Dicapryl Ether CetiolOE/BASF 20.0 Isosorbide Disunflowerseedate HydraDynol ® IDL/Sytheon 4.0(present invention) Phenylethyl Benzoate X-Tend 226/Ashland 4.8Tocopheryl Acetate Vitamin Acetate/BASF 0.20 Silicone Polyester 1Cosmosurf DGSi/Ultra 2.0 chemical Phase B Avobenzone Eusolex 9020/EMDChemicals 2.0 Trimethoxybenzylidene Synoxyl ® HSS/Sytheon 2.0Pentanedione Homosalate Eusolex HMS/EMD Chemicals 10.0 Octyl SalicylateEusolex OS/EMD Chemicals 5.0 Total 100

Without further elaboration, it is believed that one skilled in the art,using the preceding description, can utilize the present invention toits fullest extent. Furthermore, while the present invention has beendescribed with respect to aforementioned specific embodiments andexamples, it should be appreciated that other embodiments, changes andmodifications utilizing the concept of the present invention arepossible, and within the skill of one in the art, without departing fromthe spirit and scope of the invention. The preceding preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

I claim:
 1. A method of treating atopic dermatitis and/or psoriasis saidmethod comprising applying to skin suffering from or manifestingsymptoms of atopic dermatitis and/or psoriasis an efficacious amount ofone or more dilinoleate esters of 1,4:3,6-dianhydrohexitols.
 2. Themethod of claim 1 wherein the dilineolate esters are selected fromisosorbide dilinoleate, isomannide dilinoleate, isoiodide dilinoleate,and combinations of any two or all three.
 3. The method of claim 1wherein at least 50 mole percent of the dilinoleate ester is isosorbidedilinoleate.
 4. The method of claim 1 wherein the dilinoleate ester isisosorbide dilinoleate.
 5. The method of claim 1 wherein the dilinoleateester is applied in combination with one or more caprylate esters of1,4:3,6-dianhydrohexitols.
 6. The method of claim 5 wherein thecaprylate ester is isosorbide dicaprylate.
 7. The method of claim 1wherein the dilinoleate ester(s) is in a dermatologically acceptablecarrier.
 8. A method of treating atopic dermatitis and/or psoriasis saidmethod comprising applying to skin suffering from or manifestingsymptoms of atopic dermatitis and/or psoriasis a composition comprisingan efficacious amount of a mixture of 1,4:3,6-dianhydrohexitol diestersof linoleic acid with 1,4:3,6-dianhydrohexitol diesters of oleic acid,1,4:3,6-dianhydrohexitol diesters of linolenic acid or both; providedthat at least 40 mole percent of the 1,4:3,6-dianhydrohexitol diestersis 1,4:3,6-dianhydrohexitol diesters of linoleic acid.
 9. The method ofclaim 8 wherein the 1,4:3,6-dianhydrohexitol diesters are selected fromisosorbide diesters, isomannide diesters, isoiodide diesters, andcombinations of any two or all three.
 10. The method of claim 8 whereinat least 50 mole percent of the 1,4:3,6-dianhydrohexitol diesters areisosorbide diesters.
 11. The method of claim 8 wherein the1,4:3,6-dianhydrohexitol diesters are isosorbide diesters.
 12. Themethod of claim 8 wherein at least 50 mole percent of the1,4:3,6-dianhydrohexitol diesters is 1,4:3,6-dianhydrohexitol diestersof linoleic acid.
 13. The method of claim 8 wherein at least 70 molepercent of the 1,4:3,6-dianhydrohexitol diesters is1,4:3,6-dianhydrohexitol diesters of linoleic acid.
 14. The method ofclaim 8 wherein at least 50 mole percent of the 1,4:3,6-dianhydrohexitoldiesters is isosorbide dilinoleate.
 15. The method of claim 8 wherein atleast 70 mole percent of the 1,4:3,6-dianhydrohexitol diesters isisosorbide dilinoleate.
 16. The method of claim 8 wherein the mixture of1,4:3,6-dianhydrohexitol diesters is formed by reacting1,4:3,6-dianhydrohexitols with mixed fatty acids obtained from oils ofsunflower, or Safflower, or Rosehip, or Hemp, or Walnut, or Sesame, orEvening Primrose, or soybean oils.
 17. The method of claim 16 whereinthe oil is sunflower oil.
 18. The method of claim 8 wherein the mixtureof 1,4:3,6-dianhydrohexitol diesters is formed by reacting isosorbidewith mixed fatty acids obtained from oils of sunflower, or Safflower, orRosehip, or Hemp, or Walnut, or Sesame, or Evening Primrose, or soybeanoils.
 19. The method of claim 18 wherein the oil is sunflower oil. 20.The method of claim 8 wherein the composition further comprises one ormore caprylate esters of 1,4:3,6-dianhydrohexitols.
 21. The method ofclaim 20 wherein the caprylate ester is isosorbide dicaprylate.
 22. Themethod of claim 8 wherein composition further comprises adermatologically acceptable carrier.
 23. The method of claim 8 whereinthe mixture of 1,4:3,6-dianhydrohexitol diesters is present in an amountof from 0.5 to 30 weight percent of the composition.